KR20200041821A - 재조합 rsv 생백신주 및 이의 제조 방법 - Google Patents
재조합 rsv 생백신주 및 이의 제조 방법 Download PDFInfo
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Abstract
본 발명은 RSV의 외피 단백질을 코딩하는 유전자가 재배열된 유전자 재조합 호흡기 세포융합 바이러스(RSV)로, RSV의 당단백질(G 단백질)과 융합 단백질 (F 단백질)을 코딩하는 유전자 사이에 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자가 삽입되거나, RSV의 F 단백질을 코딩하는 유전자가 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자로 치환된 유전자 재조합 호흡기 세포융합 바이러스(RSV)를 제공한다. 본 발명의 재조합 RSV는 RSV 백신주로 사용될 수 있고, 안정성이 뛰어나고, 안전하여 백신으로 사용할 수 있다.
Description
본 발명은 RSV 생백신주 및 이의 제조 방법에 관한 것으로, 더욱 구체적으로 재조합된 RSV 생백신 및 이의 제조 방법에 관한 것이다.
호흡기 세포융합 바이러스 (Respiratory Syncytial Virus, RSV)는 전 세계적으로 널리 유행하는 바이러스로, 호흡기 병증을 유발하며 특히 영유아의 중증 호흡기감염 사망의 주 원인이 되는 바이러스이다. 영유아가 주 감염 대상이지만, 면역력이 약화된 환자와 노인의 호흡기 질환에 감염을 유발하여 치명적인 호흡기 질병을 일으킨다고 알려졌다. 호흡기 병증 유발 원인으로는 인플루엔자에 이어 두 번째로 높지만, 1세 미만 유아에서 10만명당 RSV로 인한 연간 사망률이 인플루엔자에 비해 약 1.3~2.5배 높은 것으로 알려졌다. 2002년 WHO의 보고에 따르면 매년 RSV에 감염 되는 사람이 6천 4백만명이며, 이중 16만 명이 사망한다고 보고하였다.
RSV 질병 방어를 목적으로 처음에는 불활성화된(inactivated) 바이러스를 이용한 백신(불활화 백신)이 개발 되었으나 질병의 병증이 더 심하게 유도되는 등의 심각한 부작용(ERD (enhanced respiratory disease))의 발생으로 불활화 백신 이용은 불가능하게 되었다. 이에 연구자들이 ERD 유발이 없고, 중화 항체 유도 능력이 탁월한 백신을 개발하기 위해 노력하였다.
특히 생백신(Live vaccine)의 경우는 ERD를 유발하지 않고 중화 항체 유도 능력이 탁월하다는 장점이 있지만, RSV가 매우 불안정(metastable)하기 때문에 바이러스의 안정성(stability) 문제와 안전성(safety) 문제를 함께 고려할 때, 백신 개발에 어려움이 있었다.
RSV는 Mononegavirales 목(order), Pneumoviridae과(family)에 속하는 Orthopneumoviridae아과(subfamily)에 속해 있다. RSV는 120-200nm정도의 중간 크기의 바이러스로, envelope와 3개의 transmembrane proteins (F, G glycoproteins 및 SH protein)으로 구성된 표면구조를 가지고 있으며, 약 15,000개의 nucleotide로 이루어진 선형의 음성 가닥 RNA를 게놈(genome)으로 가지고 있다. RSV는 G 단백질에 의해 A, B의 혈청형으로 나뉘어 진다. RSV의 게놈은 11개의 단백질을 암호화(coding)하고 있으며, Structural protein과 Non-structural protein을 암호화 하는 부분 등으로 구성 되어 있다. Non-structural protein은 Nonstructural (NS)1, Nonstructural (NS)2이며 type I interferon의 antagonist로 면역 반응 회피 기작에 작용한다. Structural protein 중 fusion (F) protein, glyco (G) protein, small hydrophobic (SH) protein은 당 단백질로 바이러스의 표면을 구성하며, nucleocapsid (N) protein, phosphoprotein (P), matrix (M) protein, viral polymerase (L) 등은 바이러스 내부를 구성하거나 virus의 복제에 중요한 역할을 한다.
RSV F 단백질은 virus entry 초기 및 cell membrane과의 융합 작용을 하는 중요한 구성요소로 항원성이 높아 vaccine과 antiviral drug의 주요 대상으로 알려져 있다. 그러나 상기 F 단백질 항원은 pre-fusion형 단백질의 안정화된 형태로 생산 및 정제가 어렵고, 안정성 확보가 곤란한 문제가 있으며, 효능 유지가 쉽지 않다.
이에 본 발명의 발명자들은 F 단백질의 불안정성을 해소하고 안전한 새로운 형태의 RSV 생백신을 개발하고자 한다.
본 발명은 안정성이 높은 이종의 F 단백질을 치환 또는 삽입하여 안정성 (stability)이 우수한 생(live) RSV 백신주 개발을 하고자 한다.
본 발명은 안정성이 높은 이종의 F 단백질로 치환 또는 삽입하여 안전성이 우수한(약독화된) live RSV 백신주 개발을 하고자 한다.
본 발명은 새로운 재조합 RSV를 개발하고자 한다.
본 발명은 RSV에 대한 방어기작을 유도할 수 있는 새로운 형태의 RSV 백신을 제공하고자 한다. 본 발명은 RSV 가 갖는 G 단백질 mutation으로 인해 secreted G를 생산하지 않아, immune escaping 기작을 억제하여 효과적인 면역 시스템 가동이 가능할 수 있는 새로운 형태의 백신을 제공하고자 한다.
본 발명은 이종의 F 단백질의 삽입 또는 치환으로 2가 백신을 생산하고자 한다.
본 발명의 일 구현예는 유전자 재조합된 호흡기 세포융합 바이러스(Respiratory Syncytial Virus, RSV)를 제공한다. RSV의 외피 단백질을 코딩하는 유전자가 재배열된 유전자 재조합 호흡기 세포융합 바이러스(RSV)를 제공한다. 즉, 외부 유전자가 RSV 유전자에 삽입된 재조합 RSV 바이러스를 제공한다. 본 발명의 일 실시예는 RSV의 당단백질(G 단백질)과 융합 단백질 (F 단백질)을 코딩하는 유전자 사이에 RSV가 아닌, 다른 바이러스로부터 유래한 F 단백질을 삽입하거나 RSV의 F 단백질 대신 치환된, 유전자 재조합 호흡기 세포융합 바이러스를 제공한다. 구체적으로, ① Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자가 삽입되거나, ② RSV의 F 단백질을 코딩하는 유전자가 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자로 치환될 수 있다. 상기 Paramyxoviridae, 또는 Pneumoviridae 바이러스과(family)의 이종 바이러스는 바이러스 속(genus) Aquaparamyxovirus, Avulavirus, Ferlavirus, Henipavirus, Morbillivirus, Respirovirus, Rubulavirus, Metapneumovirus, 및 Orthopneumovirus로 이루어진 군에서 선택된 어느 하나 이상일 수 있으며, 바람직하게는 홍역 바이러스(Measles virus), 및 뉴캐슬병 바이러스(Newcastle disease virus)로 이루어진 군에서 선택된 어느 하나 이상일 수 있다. 상기 유전자 재조합 호흡기 세포융합 바이러스(RSV)는 서열번호 1의 인간 RSV A 바이러스주를 기본으로 하여, 서열번호 3을 갖는 RSV 재조합 백본(backbone)으로 하여 상기 RSV A 바이러스주의 외피 단백질을 코딩하는 유전자(G 단백질과 F 단백질 발현 도메인)가 재배열된 재조합 RSV일 수 있다. 바람직하게 서열번호 4 내지 7의 cDNA서열을 갖는다. RSV의 anti-genome에 제한 효소 서열이 추가된 서열은 서열번호 2로 나타냈다.
본 발명의 다른 구현예는 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드를 포함하는 발현 벡터를 포함하여 약독화된 재조합 RSV를 제조하는 방법을 제공한다. 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드를 포함하는 제1 발현 벡터; 및 N, P, L, 및 M2-1 단백질로 이루어진 군에서 선택된 어느 하나 이상의 단백질을 코딩하는 폴리뉴클레오티드를 포함하는 제2 발현 벡터를 함께 발현시켜 재조합 RSV를 생산할 수 있다. 상기 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드는 이종의 바이러스로부터 유래된 단백질의 전체 또는 일부 도메인을 암호화하는 폴리뉴클레오티드가 포함된다. 상기 제1 발현 벡터에 포함되는 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드는 서열번호 4 내지 7 중에서 선택된 어느 하나일 수 있다. 상기 서열번호 4 내지 7 중에서 선택된 어느 하나의 폴리뉴클레오티드는 cDNA일 수 있다. 상기 제1 발현 벡터는 pCC1 플라스미드에 상기 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드가 포함될 수 있다.
본 발명의 일 구현예는 재조합 RSV 발현벡터를 제공한다. 상기 발현벡터는 RSV의 당단백질(G 단백질)과 융합 단백질 (F 단백질)을 코딩하는 유전자를 포함하되, 상기 G 단백질과 F 단백질을 코딩하는 유전자 사이에 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자가 삽입되거나, RSV의 융합 단백질 (F 단백질)을 코딩하는 유전자 대신 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자로 치환된 재조합 RSV 유전자가 포함될 수 있다. 상기 재조합 RSV 유전자는 서열번호 4 내지 7 중에서 선택된 어느 하나일 수 있다. 상기 재조합 RSV 발현용 벡터는 T7 프로모터, 해머헤드 라이보좀, 재조합 RSV 유전자, 헤파티티스 델타 바이러스 라이보좀; 및 T7 종결자를 순서대로 포함한다. 상기 Paramyxoviridae, 또는 Pneumoviridae 바이러스과(family)의 이종 바이러스는 바이러스 속(genus) Aquaparamyxovirus, Avulavirus, Ferlavirus, Henipavirus, Morbillivirus, Respirovirus, Rubulavirus, Metapneumovirus, 및 Orthopneumovirus로 이루어진 군에서 선택된 어느 하나 이상일 수 있으며, 바람직하게는 홍역 바이러스(Measles virus), 및 뉴캐슬병 바이러스(Newcastle disease virus)로 이루어진 군에서 선택된 어느 하나 이상일 수 있다.
본 발명의 다른 구현예는 본 발명의 일 구현예에 따른 유전자 재조합 호흡기 세포융합 바이러스(RSV) 및 약학적으로 허용 가능한 담체를 포함하는 약독화된 RSV 생백신 조성물을 제공한다. 상기 생백신 조성물을 인체에 투여하여 호흡기 세포융합 바이러스(RSV) 감염을 예방하는 방법을 제공한다.
본 발명은 live RSV 바이러스주를 제공하며, RSV 유전체에 이종 바이러스로부터 유래된 F 단백질의 전부 또는 일부 도메인을 암호화하는 폴리뉴클레오티드가 삽입된 재조합 호흡기 세포융합 바이러스(RSV)이며, 상기 폴리뉴클레오티드는 i) RSV F 단백질의 일부 도메인을 암호화하는 폴리뉴클레오티드 대신 삽입되거나, ii) RSV 유전자를 구성하는 폴리뉴클레오티드의 임의의 어느 한 부분에 삽입된다. 본 발명의 재조합 RSV는 RSV 백신주로 사용될 수 있고, 안정성이 뛰어나고, 안전하여 백신으로 사용할 수 있다.
이하에서 구체적으로 설명한다.
본 발명은 RSV 의 F 단백질을 코딩하는 유전자를 이종의 바이러스의 F 단백질 코딩 유전자로 치환하거나, 이종의 바이러스의 F 단백질 코딩 유전자를 추가로 도입한 새로운 형태의 RSV 생백신을 제공하고자 한다. [용어의 정의]
“재조합된(Recombinant)”은 하나의 생물체 안에 유전 형질이 다른 세포가 함께 존재하는 경우를 의미할 수 있으며, 특히 본원에서 사용된 “재조합된”은 하나의 유전적 백본(backbone)을 기초로 상이한 개체의 유전적 정보(핵산)가 삽입되어 새로운 유전적 변이가 발생되는 경우를 의미한다.
재조합 RSV라 함은 재조합 발현체계로부터 직간접적으로 유래되거나 또는 그들로부터 생산된 바이러스나 서브바이러스입자로부터 증식된 RSV 또는 RSV-유사 바이러스를 의미한다. 재조합 발현체계는 재조합 발현벡터를 포함하는데, 이는 RSV 유전자의 발현에서 조절기능을 가지는 적어도 하나의 유전적 구성요소 (element) 또는 구성요소들의 조합체를 포함하는, 기능적으로 연결된 전사 단위를 포함하며, 구성요소의 예로는 프로모터, RSV mRNA로 전사되는 구조 또는 코딩 서열, 적절한 전사 개시와 종결 서열이 있다.
본원에서 사용된 “유전체(genome)”는 한 개체의 유전자(gene)의 총 염기서열이며, 한 생물체가 지닌 모든 유전정보의 집합체를 의미한다. 예를 들어 바이러스의 유전체는 바이러스 전체의 모든 유전정보서열을 아우르는 의미로 사용된다.
본원에서 사용된 “유전자(gene)”는 단백질을 암호화하는 부분으로 이해될 수 있으며, DNA 또는 RNA 일 수 있다.
본원에서 사용된 “도입”의 의미는 본래 가진 것에서 새로운 것이 추가되는 것을 의미하는 것으로, 도입으로 인해 유전자의 변이가 유발될 수 있고, 결실, 치환, 또는 삽입 등이 일어날 수 있다.
예를 들어, 본원에서 “유전체에 새로운 유전자가 도입되었다”는 의미는 본래 개체가 가지고 있는 전체 유전자 염기 서열 중 일부가 새로운 개체로부터 유래된 유전자로 치환되거나 삽입될 수 있다는 것을 의미할 수 있다. 이러한 도입으로 인해 본래 개체(예를 들어 backbone)가 갖는 유전체 염기서열보다 길어질 수도 있고, 짧아질 수도 있고, 길이가 유지될 수도 있다.
본원에서 사용된 “백신주”는 백신균주(vaccine strain)으로도 불리며, 백신으로 이용되기 위해 분리된 바이러스 집단을 의미한다.
본원에서 사용된 “약독화된(attenuated) 생백신”이란 약화된 호흡기 세포융합 바이러스(RSV)로 만드는 백신으로, 병원체가 여전히 생물학적 활성이 있기는 하나 숙주 내에서 질병을 잘 유발하지 않을 만큼 약화된 독성을 가지는 백신을 의미한다.
본원에서 사용된 “안티게놈(anti-genome)”이란 자손 RSV 게놈의 합성을 위한 주형으로 작용하는 상보적인 (+)센스 폴리뉴클레오타이드 분자를 의미한다. 천연 RSV는 일반적으로 (-) 센스 폴리뉴클레오티드 분자를 포함하며, 이는 상보적인 바이러스 mRNA를 통해 바이러스 단백질, 예를 들어, 당단백질(G), 융합(F), N, P 등을 코드한다. RSV 게놈 또는 안티게놈을 코딩하는 cDNA의 재조합으로 약독화된 RSV 생백신주를 제조할 수 있다.
본원에서 사용된 “단백질을 암호화하는 유전자” 또는 “단백질 코딩 유전자”는 단백질을 생성하는 유전자를 의미한다.
본 발명의 일 구현예는 RSV 유전체를 기본으로 이종 바이러스의 F 단백질을 삽입하거나, 또는 RSV의 F 단백질과 이종 바이러스의 F 단백질을 치환하여 안정성 및 안전성이 우수한 live RSV 백신주를 제공한다.
본 발명의 일 구현예는 RSV 유전체에 이종 바이러스로부터 유래된 F 단백질의 일부 도메인을 암호화하는 폴리뉴클레오티드가 삽입된 재조합 호흡기 세포융합 바이러스(RSV) 백신주를 제공한다.
상기 폴리뉴클레오티드는
i) RSV F 단백질의 일부 도메인을 암호화하는 폴리뉴클레오티드 대신 삽입되거나, ii) RSV F 단백질과 G 단백질 도메인을 암호화하는 폴리뉴클레오티드 사이에 삽입될 수 있다.
도 2는 RSV의 F 단백질 중 일부 도메인을 암호화는 폴리뉴클레오티드가 외래 바이러스로부터 유래된 F 단백질 중 일부 도메인으로 치환된 형태를 보여주기 위한 그림이다.
도 3은 RSV의 F 단백질을 암호화하는 폴리뉴클레오티드는 그대로 유지하고, 외래 바이러스로부터 유래된 F 단백질 중 일부 도메인이 삽입된 형태를 보여주기 위한 그림이다.
상기 이종 바이러스는 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자로 치환될 수 있다. 상기 Paramyxoviridae, 또는 Pneumoviridae 바이러스과(family)의 이종 바이러스는 바이러스 속(genus) Aquaparamyxovirus, Avulavirus, Ferlavirus, Henipavirus, Morbillivirus, Respirovirus, Rubulavirus, Metapneumovirus, 및 Orthopneumovirus로 이루어진 군에서 선택된 어느 하나 이상일 수 있으며, 바람직하게는 홍역 바이러스(Measles virus), 및 뉴캐슬병 바이러스(Newcastle disease virus)로 이루어진 군에서 선택된 어느 하나 이상일 수 있다. 특히 상기 홍역 바이러스 및 뉴캐슬병 바이러스는 바이러스의 안정성 및 생백신 바이러스주의 안전성을 높일 수 있다.
바람직하게 본 발명의 기본이 되는 RSV 바이러스 유전체는 서열번호 1의 야생형 인간 RSV A 바이러스주를 이용할 수 있다. RSV 바이러스주는 RSV A 주, RSV B 주, HRSV A 주, HRSV B 주, BRSV 주, 조류 RSV 주 등 다양하지만, 본 발명의 목적상 외래 유전자가 삽입되는 RSV 기본 백본은 RSV A 바이러스주가 바람직할 수 있다. 상기 RSV A 바이러스주를 이용하여 외래 유전자가 도입되는 경우 생산된 재조합 바이러스의 안정성 및 안전성이 우수하고, 돌연변이 발생율이 적을 수 있다.
본 발명의 일 구현예는 이종의 바이러스로부터 유래된 F 단백질의 일부 도메인을 암호화하는 폴리뉴클레오티드가 포함된 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드를 포함하는 제1 발현 벡터 및
N, P, L, 및 M2-1 단백질로 이루어진 군에서 선택된 어느 하나 이상의 단백질을 코딩하는 폴리뉴클레오티드를 포함하는 제2 발현 벡터를 함께 발현시켜 재조합 RSV를 생산하는 약독화된 RSV 백신주를 제조하는 방법을 제공한다. 상기 제1 발현 벡터는 pCC1, pBR322, pUC, pcDNA3.1 등이 사용될 수 있으나, cloning 과정 중 사이즈나 세포독성 방지 등을 고려할 때, 본 목적상 pCC1이 바람직하게 사용될 수 있다. 상기 제2 발현 벡터는 pCI neo 벡터를 이용할 수 있으나, 이에 제한되지 않는다.
RSV는 negative sense RNA 바이러스로 reverse genetics를 이용하여 in vitro에서 바이러스 생산 시, 유전자 합성에 필요한 별도의 헬퍼 유전자(helper gene)가 필요하다. 재조합된 RSV 안티게놈 및 각각의 N, P, L, M2-1 단백질을 암호화하는 폴리뉴클레오타이드를 형질감염(transfection), 일렉트로포레이션(electroporation), 기계적인 삽입, 형질도입과 같은 방법으로 세포에 도입할 수 있다. Vero cell, Hep 2 cell, MRC 5 cell 등과 같은 세포에서 바이러스의 감염이 일어날 수 있으며, Vero cell 에서 본 발명의 재조합된 RSV 바이러스주 생산이 유리할 수 있다.
재조합된 RSV 안티게놈 및 각각의 N, P, L, M2-1 단백질을 암호화하는 폴리뉴클레오타이드를 세포에 도입하는 방법은 업계에서 일반적으로 사용하는 방법이 이용될 수 있으며, 특별히 제한되지 않는다.
다른 구현예에서 세포외에서 RSV 안티게놈 RNA를 합성하여 RSV 단백질을 발현하는 세포에 형질감염하여 합성할 수도 있다.
재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드를 제1 발현 벡터에 포함시키고, 헬퍼 유전자를 제1 발현 벡터와 다른 벡터(제2 발현 벡터)에 포함시킬 수도 있고, 같은 벡터에 포함시킬 수도 있다.
제1 발현 벡터에 포함되는 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드는 서열번호 4 내지 7 중에서 선택된 어느 하나의 폴리뉴클레오티드가 포함될 수 있으며, 상기 서열번호 4 내지 7 중에서 선택된 어느 하나의 폴리뉴클레오티드는 cDNA일 수 있다.
상기 제1 발현 벡터는 pCC1 플라스미드에 상기 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드가 포함된 것일 수 있으며, 조합을 용이하게 할 목적으로 돌연변이를 유발하거나, 제한효소 자리를 변형하거나 또는 조절된 제한효소 자리를 포함하는 합성된 폴리링커를 삽입하여 벡터를 변형할 수도 있다.
본 발명의 pCC1 플라스미드는 재조합된 RSV 안티게놈을 안정화할 수 있다.
바람직하게 재조합된 RSV 안티게놈을 포함하는 제1 발현 벡터는 T7 프로모터, 해머헤드 라이보좀(hammerhead ribozyme), RSV 안티게놈, 헤파티티스 델타 바이러스 라이보좀(hepatitis delta virus ribozyme), 및 T7 종결자를 포함하는 폴리뉴클레오티드의 cDNA가 포함된 발현벡터일 수 있다.
상기 RSV 안티게놈은 홍역 바이러스(Measles virus), 뉴캐슬병 바이러스(Newcastle disease virus), 및 파라인플루엔자 바이러스 (PIV)의 F 단백질을 포함하되, 상기 F 단백질의 트랜스 멤브레인(TM) 및 사이토플라스믹 테일(CT) 도메인을 암호화하는 폴리뉴클레오티드는 RSV로부터 유래된 것을 사용할 수 있지만, 상기 바이러스로부터 유래된 것을 사용할 수도 있다. 본 발명의 일 구현예는 상기 방법에 따라 제조된 약독화된 RSV 백신주를 제공한다.
본 발명의 일 구현예는 본 원의 RSV 바이러스주; 및 약학적으로 허용가능한 담체를 포함하는 RSV 생백신을 제공한다.
본 발명의 일 구현예에 의해 제조된 재조합된 RSV 백신주는 백신 용도로 사용할 때, 본 발명에 따라 제조된 바이러스를 백신제제로 직접적으로 사용하거나, 동결건조시켜 사용하거나, 액체에 혼합하여 사용할 수 있다.
본 발명의 백신 조성물은 이 조성물을 투여받는 척추동물에 해로운 면역 반응을 자체로 유발하지 않는 임의의 약학적 물질을 포함하고, 재조합 RSV 백신주와 함께 과도한 독성 없이 투여될 수 있는 임의의 적절한 희석제 또는 부형제를 포함하는 약학적으로 허용가능한 담체를 포함한다. "약학적으로 허용가능한"이란 용어는 미국 약전, 유럽 약전 또는 척추동물 및 더욱 구체적으로 인간에 사용하기 위한 다른 일반적으로 인식된 약전에 나열되는 것을 의미한다. 본 발명의 RSV F 항원은 RSV 바이러스의 하나 이상의 균주에 대항하여 면역 반응을 자극하는데 충분한 유효량 또는 양(위에서 정의함)으로 투여된다. 이런 조성물은 척추동물에서 보호성 면역반응을 유도하기 위한 백신 및/또는 면역원성 조성물로서 사용될 수 있다.
한 비-제한적인 실시태양에서, 백신에 포함되는 재조합 RSV 항원의 농도는 적어도 약 10㎍/mL, 약 20㎍/mL, 약 30㎍/mL, 약 40㎍/mL, 약 50㎍/mL, 약 60㎍/mL, 약 100㎍/mL, 약 200㎍/mL, 또는 약 500㎍/mL이다. 특정 양태에서, 면역원의 농도는 약 10㎍/mL 내지 약 1mg/mL, 또는 약 20㎍/mL 내지 약 500㎍/mL, 또는 약 30㎍/mL 내지 약 100㎍/mL 또는 약 30㎍/mL 내지 약 50㎍/mL이다. 다른 실시태양에서 면역원의 농도는 10㎍/mL 내지 200㎍/mL 포함될 수 있다.
본 발명의 백신 또는 면역원 조성물은 RSV 에 대항하여 면역 반응을 유도하도록 동물에게 투여될 수 있다. 한 실시태양에서, 동물은 인간이다. 통상적으로, 복용량은, 예를 들어, 나이, 신체 조건, 체중, 나이, 식품, 투여 시간 및 다른 임상적 인자를 기초로 이 범위 내에서 조절될 수 있다. 따라서, 본 발명은 유효량의 면역원을 상기 제제에 첨가하는 단계를 포함하여, 피험자의 감염 또는 이의 적어도 하나의 증상에 대해 실질적 면역성을 유발하는 백신 또는 면역원 조성물을 제제화하는 방법을 포함한다. 1회 복용량에 의한 실질적 면역성의 자극이 바람직하지만, 원하는 효과를 얻기 위해서, 동일하거나 다른 경로를 통해 추가 복용량이 투여될 수 있다. 신생아 및 유아에서, 예를 들어, 충분한 수준의 면역을 유발하기 위해 복수의 투여가 필요할 수 있다. 투여는 감염에 대항하는 충분한 수준의 보호를 유지하기 위해 필요한 경우, 유년 시기에 걸쳐 간격을 주고 계속될 수 있다. 한 실시태양에서, 피험자에서 바이러스 감염 또는 이의 적어도 하나의 증상에 대해 실질적 면역성을 유도하는 방법은 적어도 1회 유효량의 RSV 재조합 F 단백질 또는 이의 단편 또는 집합체를 투여하는 단계를 포함한다. 백신 및/또는 면역원 제제를 투여하는 방법은 비경구 투여(예를 들어, 내피, 근육내, 정맥 및 피하), 경막외 및 점막(예를 들어, 비강 및 경구 또는 폐 경로 또는 좌약)을 포함하나 이에 한정되지 않는다. 특정 실시태양에서, 상기 조성물은 근육내, 정맥, 피하, 경구 또는 피내로 투여된다. 상기 조성물은, 예를 들어, 주입 또는 일시 주사, 상피 또는 점막 안쪽(예를 들어, 구강 점막, 결장, 결막, 비인 강, 인두중앙부, 질, 요로, 방광, 장 점막 등)을 통한 흡수에 의해 임의의 편리한 경로에 의해 투여될 수 있고 다른 생물학적으로 활성인 물질과 함께 투여될 수 있다. 투여는 전신 또는 국부적 일 수 있다. 예방 백신 제제는 바늘 및 주사를 사용하여 피하 또는 근육내 주사 또는 바늘 없는 주사 장치에 의해 전신으로 투여된다. 선택적으로, 백신 제제는 상기도 속으로의 방울, 큰 입자 에어로졸(약 10 마이크론보다 큼) 또는 분사에 의해 비강으로 투여된다. 전달의 상기 경로 중 임의의 것은 면역 반응을 일으키는 반면에, 비강 투여는 바이러스의 침투 위치에서 점막 면역성을 유발하는 증가된 효과를 제공한다. 또 다른 실시태양에서, 백신 및/또는 면역원성 제제는 면역화의 부위에 면역 반응을 유발하도록 점막 조직을 표적으로 하는 방식으로 투여될 수 있다. 투여 부위는 제한되지 않는다.
본 발명의 일 구현예는 본 원의 RSV 백신주를 인체에 투여하여 호흡기 세포융합 바이러스(RSV) 감염을 예방하는 방법을 제공한다.
본 발명은 안정성이 높은 이종의 F 단백질을 치환 또는 삽입하여 안정성 (stability)이 우수한 생(live) RSV 백신주를 제공한다. 일반적으로 생백신이 갖고 있는 불안전성 및 불안정성을 해소하면서도 야생형 RSV 와 비슷한 수준의 항체 생성율을 갖는 새로운 재조합 RSV 바이러스주를 제공한다.
본 발명은 안정성이 높은 이종의 F 단백질로 치환 또는 삽입하여 안전성이 우수한(약독화된) live RSV 백신주를 제공한다.
본 발명은 RSV에 대한 방어기작을 유도할 수 있는 새로운 형태의 RSV 백신을 제공한다.
본 발명은 RSV 가 갖는 G 단백질 mutation으로 인해 secreted G를 생산하지 않아, immune escaping 기작을 억제하여 효과적인 면역 시스템 가동이 가능할 수 있는 새로운 형태의 백신을 제공한다.
본 발명은 이종의 F 단백질의 삽입 또는 치환으로 2가 백신을 생산할 수 있다.
본 발명은 새로운 재조합 RSV를 제공한다.
도 1은 RSV Genome을 도식화한 그림이다.
도 2는 RSV genome에서 F 단백질 부위를 절단(화살표는 절단 부위를 나타냄)하고 이종의 바이러스(예를 들어, NDV)의 F 단백질로 치환한 형태를 보여주는 개략도이다.
도 3은 RSV genome에서 G 단백질과 F 단백질 사이에 이종의 바이러스(예를 들어, MV)의 F 단백질을 추가한 형태를 보여주는 개략도이다.
도 4는 서열번호 3의 백본에서 MluI 및 ApaI 부위를 절단하여 외부 바이러스로부터 유래된 F 단백질을 삽입한 그림을 보여준다. ③ final construct의 G GE는 G 단백질 gene end region을, F GS는 F 단백질 gene starting region을, F GE는 F 단백질 gene end region을 나타낸다. MV 또는 NDV의 F 단백질이 삽입되나, F 단백질의 T 및 C 도메인은 RSV 의 것을 이용한다.
도 5는 서열번호 3의 백본에서 MluI 및 MluI 부위를 절단하여 외부 바이러스로부터 유래된 F 단백질을 삽입한 그림을 보여준다. MluI 및 MluI 절단 부위는 RSV의 G 단백질과 F 단백질 사이에 위치한다. ③ final construct의 G GE는 G 단백질 gene end region을, F GS는 F 단백질 gene starting region을, F GE는 F 단백질 gene end region을 나타낸다. MV 또는 NDVF의 F 단백질이 삽입되나, 추가되는 F 단백질의 T 및 C 도메인은 RSV의 것을 이용한다.
도 6은 본 발명의 재조합 RSV 바이러스의 cDNA를 벡터에 클로닝한 모식도를 보여준다.
도 7은 재조합 RSV의 각 세포별(HEp2 cell, Vero cell, MRC5 cell) 증식속도 및 증식 titer 비교를 통해 약독화를 보여주는 결과이다. Wild type RSV에 비해 백신주의 증식 속도 및 titer가 감소하였다.
도 8은 재조합 RSV의 마우스내에서 증식속도 및 증식 titer 비교를 통해 약독화를 보여주는 결과이다. Wild type RSV에 비해 백신주의 증식 속도 및 titer가 감소하였다.
도 9는 온도에 따른 재조합 RSV의 안정성 결과를 보여준다. 4℃, 37℃, 60℃ 모두에서 wild type RSV에 비해 열 안정성이 높아졌다.
도 10은 재조합 RSV의 마우스 면역 시험 결과를 보여주는 것으로, 총항체가 및 중화 항체가를 확인한 결과이다. Mock을 제외한 모든 그룹에서 충분한 항원 특이 및 중화 항체가 유도되었다. 다만, formalin으로 불화화된 wild type virus인 G7의 경우 상대적으로 매우 낮은 총항체가와 중화항체가를 보였다.
RSV backbone 은 wtRSVA_TH10654,
RSV backbone- MV F 치환은 cRSVA_MVF_S,
RSV backbone- NDV F 치환은 cRSVA_NDVF_S,
RSV backbone- MV F 삽입은 cRSVA_MVF_A, 그리고
RSV backbone- NDV F 삽입은 cRSVA_NDVF_A로 나타내었다.
도 10의 Mock는 G1으로, WtRSVA는 G2로, cRSVA_MVF_S는 G3으로, cRSVA_NDVF_S는 G4로, cRSVA_MVF_A는 G5로, cRSVA_NDVF_A는 G6로, 그리고 FIwtRSVA는 G7으로 나타냈다.
도 11은 재조합 RSV 면역후 wild RSV를 challenge하여 방어력을 측정한 결과이다. Mock를 제외한 모든 그룹에서 충분한 방어면역을 유도하였다. 다만, formalin으로 불화화된 wild type virus인 G7의 경우 다소 부족한 방어면역 효과를 나타내었다.
도 12는 NDV 면역원성 시험 결과 및 중화항체가 결과를 보여준다,
도 13은 MV 면역원성 시험 결과 및 중화항체가 결과를 보여준다.
도 12 및 13의 Mock는 G1으로, WtRSVA는 G2로, cRSVA_MVF_S는 G3으로, cRSVA_NDVF_S는 G4로, cRSVA_MVF_A는 G5로, cRSVA_NDVF_A는 G6로, 그리고 FIwtRSVA는 G7으로 나타냈다.
도 2는 RSV genome에서 F 단백질 부위를 절단(화살표는 절단 부위를 나타냄)하고 이종의 바이러스(예를 들어, NDV)의 F 단백질로 치환한 형태를 보여주는 개략도이다.
도 3은 RSV genome에서 G 단백질과 F 단백질 사이에 이종의 바이러스(예를 들어, MV)의 F 단백질을 추가한 형태를 보여주는 개략도이다.
도 4는 서열번호 3의 백본에서 MluI 및 ApaI 부위를 절단하여 외부 바이러스로부터 유래된 F 단백질을 삽입한 그림을 보여준다. ③ final construct의 G GE는 G 단백질 gene end region을, F GS는 F 단백질 gene starting region을, F GE는 F 단백질 gene end region을 나타낸다. MV 또는 NDV의 F 단백질이 삽입되나, F 단백질의 T 및 C 도메인은 RSV 의 것을 이용한다.
도 5는 서열번호 3의 백본에서 MluI 및 MluI 부위를 절단하여 외부 바이러스로부터 유래된 F 단백질을 삽입한 그림을 보여준다. MluI 및 MluI 절단 부위는 RSV의 G 단백질과 F 단백질 사이에 위치한다. ③ final construct의 G GE는 G 단백질 gene end region을, F GS는 F 단백질 gene starting region을, F GE는 F 단백질 gene end region을 나타낸다. MV 또는 NDVF의 F 단백질이 삽입되나, 추가되는 F 단백질의 T 및 C 도메인은 RSV의 것을 이용한다.
도 6은 본 발명의 재조합 RSV 바이러스의 cDNA를 벡터에 클로닝한 모식도를 보여준다.
도 7은 재조합 RSV의 각 세포별(HEp2 cell, Vero cell, MRC5 cell) 증식속도 및 증식 titer 비교를 통해 약독화를 보여주는 결과이다. Wild type RSV에 비해 백신주의 증식 속도 및 titer가 감소하였다.
도 8은 재조합 RSV의 마우스내에서 증식속도 및 증식 titer 비교를 통해 약독화를 보여주는 결과이다. Wild type RSV에 비해 백신주의 증식 속도 및 titer가 감소하였다.
도 9는 온도에 따른 재조합 RSV의 안정성 결과를 보여준다. 4℃, 37℃, 60℃ 모두에서 wild type RSV에 비해 열 안정성이 높아졌다.
도 10은 재조합 RSV의 마우스 면역 시험 결과를 보여주는 것으로, 총항체가 및 중화 항체가를 확인한 결과이다. Mock을 제외한 모든 그룹에서 충분한 항원 특이 및 중화 항체가 유도되었다. 다만, formalin으로 불화화된 wild type virus인 G7의 경우 상대적으로 매우 낮은 총항체가와 중화항체가를 보였다.
RSV backbone 은 wtRSVA_TH10654,
RSV backbone- MV F 치환은 cRSVA_MVF_S,
RSV backbone- NDV F 치환은 cRSVA_NDVF_S,
RSV backbone- MV F 삽입은 cRSVA_MVF_A, 그리고
RSV backbone- NDV F 삽입은 cRSVA_NDVF_A로 나타내었다.
도 10의 Mock는 G1으로, WtRSVA는 G2로, cRSVA_MVF_S는 G3으로, cRSVA_NDVF_S는 G4로, cRSVA_MVF_A는 G5로, cRSVA_NDVF_A는 G6로, 그리고 FIwtRSVA는 G7으로 나타냈다.
도 11은 재조합 RSV 면역후 wild RSV를 challenge하여 방어력을 측정한 결과이다. Mock를 제외한 모든 그룹에서 충분한 방어면역을 유도하였다. 다만, formalin으로 불화화된 wild type virus인 G7의 경우 다소 부족한 방어면역 효과를 나타내었다.
도 12는 NDV 면역원성 시험 결과 및 중화항체가 결과를 보여준다,
도 13은 MV 면역원성 시험 결과 및 중화항체가 결과를 보여준다.
도 12 및 13의 Mock는 G1으로, WtRSVA는 G2로, cRSVA_MVF_S는 G3으로, cRSVA_NDVF_S는 G4로, cRSVA_MVF_A는 G5로, cRSVA_NDVF_A는 G6로, 그리고 FIwtRSVA는 G7으로 나타냈다.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.
1. 야생형
RSV
A
바이러스주
준비
아래의 정보를 갖는 야생형 RSV A 바이러스주를 아래와 같이 준비하였다.
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Definition ; Human respiratory syncytial virus strain RSVA / TH_10654 / complete genome
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Accession No. ; KU950464.1
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Length ; 15232 bp
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Host ; Homo sapiens / female / 12 weeks
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Collection date ; 19-Feb-2014
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Country ; USA
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Subtype ; RSV A
서열번호 1로 나타냈다.
2. F 단백질 공여자(Donor) 바이러스 준비
F 단백질 donor로 홍역 바이러스(Measles virus (MV)), 뉴캐슬병 바이러스(Newcastle disease virus(NDV)) 를 선택하였다.
3.
RSV
안티게놈을
코딩하는 cDNA의 제조
이하의 Backbone construct A를 기본으로 하여, RSV anti-genome이 갖는 F 단백질을 암호화하는 폴리뉴클레오티드는 이종 바이러스로부터 유래된 F 단백질의 폴리뉴클레오티드로 치환 또는 삽입하여 제작하였다.
(1)
Backbone construct A의 디자인 (서열번호 3)
유전자 순서는 T7 promoter - hammerhead ribozyme - RSV anti-genome - hepatitis delta virus ribozyme - T7 terminator 순으로 한다.
5` 말단에 T7 promoter 서열(TAATACGACTCACTATAGG) 삽입하였다. T7 promotor 서열에 이어 hammerhead ribozyme 서열 (T TTTTTCGCGT CTGATGAGGC CGTTAGGCCG AAACTCCTCT CCGGAGTC)을 삽입하였다. Hammerhead ribozyme 서열에 이어 야생형 RSV anti-genome 서열을 삽입하고 아래의 변이가 적용되었다.
야생형 RSV의 anti-genome 서열을 기반으로 하여,
77nt와 78nt사이에 GCGCGCC를 삽입하여 AscI 제한효소 서열을 생성한다. (AscI 제한효소 서열은 GGCGCGCC<8 bp>인데 77nt의 서열이 G이므로 GCGCGCC<7 bp> 만 삽입하였다.)
1) 1079nt와 1080nt 사이에 CCTGCAGG (SbfI 제한 효소) 서열을 삽입한다.
2) 4600nt와 4601nt 사이에 GGCCGGCC (FseI 제한 효소) 서열을 삽입한다.
3) 4800nt와 4802nt 염기인 ATG(M)를 ATT(I) 서열로 치환한다.
4) 5639nt와 5640nt 사이에 ACGCGT (MluI 제한 효소) 서열을 삽입한다.
5) 7595nt와 7596nt 사이에 GGGCCC (ApaI 제한 효소) 서열을 삽입한다.
6) 야생형 RSV antigenome 서열에 이어 hepatitis delta virus ribozyme 서열(GGCCGGCATGGTCCCAGCCTCCTCGCTGGCGCCGGCTGGGCAACATGCTTCGGCATGGCGAATGGGAC)을 삽입한다.
7) Hepatitis delta virus ribozyme 서열에 이어 T7 terminator 서열 (TAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTG )을 삽입한다.
8) 5`최말단에 ACGCGAAAAAATGCGTACAAC 서열 삽입하고, 3`최말단에 GTTTTTGACACTTTTTTTCTCGT 서열 삽입한다. 여기서 5`최말단에 삽입된 ACGCGAAAAAATGCGTACAAC은 3' leader로 표시하고, 3`최말단에 삽입된 GTTTTTGACACTTTTTTTCTCGT은 5' trailer로 표시하였다.
디자인된 유전자 (서열번호 3)를 in vitro 합성 후 pCC1 vector에 cloning 하였다.
G 단백질 서열 중 하나의 point mutation 유도(M48I)을 도입하였다.
(2) Measles virus F 치환 construct B의 디자인 (서열번호 4)
상기 Backbone construct A 를 기본으로,
F 단백질 유전자 서열을 제거하고 대응하는 measles virus F 유전자 서열을 삽입하였다.
Measles virus인 Edmonston strain (Moraten vaccine)의 anti-genome 정보(Accession No.; AF266287.1)를 사용하였다.
Edmonston strain anti-genome에서 F 단백질 유전자는 5449 ~ 7110 서열에 해당하며, 이중 transmembrane region과 cytoplasmic tail region 서열을 제외한 5449 ~ 6939 서열을 사용하였다. Transmembrane region과 cytoplasmic tail region 서열은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 서열을 사용하였다. 5` UTR 및 3`UTR은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 F 단백질 유전자의 UTR 서열을 사용하였다.
Backbone construct A를 MluI과 ApaI 제한효소로 절단하고 디자인한 measles virus F 유전자를 삽입하였다.
(3) Newcastle disease virus F 치환 construct C의 디자인 (서열번호 5)
Backbone construct A 를 기본으로,
F 단백질 유전자 서열을 제거하고 대응하는 Newcastle disease virus F 유전자 서열을 삽입하였다.
Newcastle disease virus인 I-2 strain의 anti-genome 정보(Accession No. ; AY935499)를 사용하였다.
I-2 strain 게놈에서 F 단백질 유전자는 4544 ~ 6205 서열에 해당하며, 이중 transmembrane region과 cytoplasmic tail region 서열을 제외한 4544 ~ 6043 서열을 사용하였다. Transmembrane region과 cytoplasmic tail region 서열은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 서열을 사용하였다. 5` UTR 및 3`UTR은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 F 단백질 유전자의 UTR 서열을 사용하였다.
Backbone construct A를 MluI과 ApaI 제한효소로 절단하고 디자인한 Newcastle disease virus F 유전자를 삽입하였다.
도 4에서 도식화한 바와 같이, 상기 construct B 및 C는 제한효소 MluI/ApaI를 인식하고, Primer 1-Primer 2로 insert 증폭하였으며, Primer 1 (forward)는 5' ATAT ACGCGT gtattgttgcaaaaagccatg, Primer 2 (reverse)는 5' ATAT GGGCCC tgttttatataactataaaatagaa 이다.
(4) Measles virus F 삽입 construct D의 디자인 (서열번호 6)
Backbone construct A 를 기본으로,
G 단백질과 F 단백질 유전자 사이에 measles virus F 유전자 서열을 삽입하였다.
Measles virus인 Edmonston strain (Moraten vaccine)의 유전자 정보(Accession No. ; AF266287.1)를 사용하였다.
Edmonston strain 게놈에서 F 단백질 유전자는 5449 ~ 7110 서열에 해당하며, 이중 transmembrane region과 cytoplasmic tail region 서열을 제외한 5449 ~ 6939 서열을 사용하였다. Transmembrane region과 cytoplasmic tail region 서열은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 서열을 사용하였다. 5` UTR은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 F 단백질 유전자의 5` UTR서열을 사용하였다. 3`UTR은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 G 단백질 유전자의 3`UTR 서열을 사용하였다.
Backbone construct A를 MluI 제한효소로 절단하고 디자인한 measles virus F 유전자를 삽입한다.
(5) Newcastle disease virus F 삽입 construct E의 디자인 (서열번호 7)
Backbone construct A 를 기본으로,
G 단백질과 F 단백질 유전자 사이에 Newcastle disease virus F 유전자 서열을 삽입하였다.
Newcastle disease virus인 I-2 strain의 유전자 정보(Accession No. ; AY935499)를 사용하였다.
I-2 strain 게놈에서 F 단백질 유전자는 4544 ~ 6205 서열에 해당하며, 이중 transmembrane region과 cytoplasmic tail region 서열을 제외한 4544 ~ 6043 서열을 사용하였다. Transmembrane region과 cytoplasmic tail region 서열은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 서열을 사용하였다. 5` UTR은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 F 단백질 유전자의 5` UTR서열을 사용하였다. 3`UTR은 야생형 human respiratory syncytial virus strain RSVA / TH_10654의 G 단백질 유전자의 3`UTR 서열을 사용하였다.
Backbone construct A를 MluI 제한효소로 절단하고 디자인한 Newcastle disease virus F 유전자를 삽입하였다.
도 5에 도식화한 바와 같이, 제한효소 MluI로 인식하는 부위에 이종 바이러스 유전자를 삽입하며, Primer 1-Primer 3로 insert 증폭을 진행한다. Primer 1 (forward)는 5' ATAT ACGCGT gtattgttgcaaaaagccatg, Primer 3(reverse)는 5' ATAT ACGCGT gctttttaatgacta tcagttactaaatgcaatat 이다.
4. Helper gene의 디자인 (4종)
RSV는 negative sense RNA 바이러스로 reverse genetics를 이용하여 in vitro에서 바이러스 생산 시, 유전자 합성에 필요한 helper gene (RSV의 N, P, L, M2-1 단백질 암호화 유전자)을 함께 넣어 준다.
(1) N 단백질 유전자는 야생형 human respiratory syncytial virus strain RSVA / TH_10654 anti-genome의 1119 ~ 2294 서열을 pCI neo vector에 제한효소 XhoI과 MluI을 이용하여 cloning한다.
(2) P 단백질 유전자는 야생형 human respiratory syncytial virus strain RSVA / TH_10654 anti-genome의 2326 ~ 3051 서열을 pCI neo vector에 제한효소 XhoI과 MluI을 이용하여 cloning한다.
(3) M2-1 단백질 유전자는 야생형 human respiratory syncytial virus strain RSVA / TH_10654 anti-genome의 7647 ~ 8231 서열을 pCI neo vector에 제한효소 XhoI과 MluI을 이용하여 cloning한다.
(4) L 단백질 유전자는 야생형 human respiratory syncytial virus strain RSVA / TH_10654 anti-genome의 8539 ~ 15036 서열을 pCI neo vector에 제한효소 XhoI과 MluI을 이용하여 cloning한다.
각각 N 단백질 유전자는 서열번호 8, P 단백질 유전자는 서열번호 9, M2-1 단백질 유전자는 서열번호 10, L 단백질 유전자는 서열번호 11로 나타냈다.
5. 바이러스 rescue
BHK cell을 6well plate에 4 x 105 cell/well 농도로 준비하였다.
다음 날, T7 polymerase 발현 vector 2ug, RSV full length anti-genome vector 2ug, helper gene vector 4종(N, P, M2-1, L) 각 1ug의 총 6종의 plasmid를 동시에 lipofectamine3000 10ul와 혼합하고 10분간 반응시킨 뒤 BHK cell에 transfection하였다. 세포에 균일하게 적용될 수 있도록 방울방울 떨어트리고 2~3회 흔들어 잘 혼합될 수 있도록 한다.
5일간 37℃ CO2 인큐베이터에서 세포를 배양하고 배양액을 회수하여 새롭게 준비된 6 well plate의 Vero cell(3 x 105/well)에 1ml씩 감염하여 다시 5일간 배양하고 바이러스 용액을 얻었다. 이와 같은 방식으로 재조합 wild type RSV 1종, RSV 백신주 4종을 생산하였다.
해당 기술은 통상적으로 연구자들이 RSV 바이러스를 rescue 하기 위해 주로 사용하는 실험법으로 특별한 기술적 한계점은 없다. 본 연구에서는 여러 유사 기술 중 특히 “ BAC-Based Recovery of Recombinant Respiratory Syncytial Virus (RSV); Reverse Genetics of RNA Viruses pp 111-124” 그리고 “RNA Virus Reverse Genetics and Vaccine Design; Viruses 2014, 6, 2531-2550 의 자료를 참고하여 실험에 응용하였다. 배양액을 회수하여 IFA, RT-PCR, 유전자 서열 분석을 통해 바이러스를 검출하였다.
①
RSV backbone strain ; wtRSVA_TH10654(Wild type control)
②
RSV backbone strain- MV F 치환 ; cRSVA_MVF_S(변이 바이러스)
③
RSV backbone strain - NDV F 치환 ; cRSVA_NDVF_S(변이 바이러스)
④
RSV backbone strain- MV F 삽입 ; cRSVA_MVF_A(변이 바이러스)
⑤
RSV backbone strain- NDV F 삽입 ; cRSVA_NDVF_A(변이 바이러스)
6.
In vitro
약독화
시험
5종의 바이러스를 Vero cell, HEp2 cell, MRC-5에 0.1 MOI를 감염하고 9일간 배양하였다. 매 1일 간격으로 바이러스 배양액을 수집하고 q-PCR을 이용하여 virus titer를 분석하였다.
그 결과, 도 7에 나타난 바와 같이, 야생형 바이러스에 비해 변이바이러스인 백신주가 증식속도와 증식 titer가 감소하여 약독화 되었음을 확인하였다. 이를 통해 재조합된 바이러스들은 생백신주로 사용될 수 있음을 알 수 있다. DPI는 days post infection을 의미한다.
7.
In
vivo
약독화
시험
5종의 바이러스를 BALB/c 마우스의 IN route를 통해 101 ~ 107 pfu/mouse 의 농도별로 투여하였다. 1~7일 차 blood에서 q-PCR을 이용하여 viremia를 검출하여 약독화 되었음을 확인하였다.
그 결과는 도 8에 나타냈다. 도 8에서 확인할 수 있듯이 야생형 RSV A 바이러스와 비교해 접종 후 in vivo 에서 약독화되었음을 알 수 있고, 이를 통해 재조합된 RSV는 새로운 바이러스주로 사용될 수 있음을 확인하였다.
8.
바이러스 안정성 시험
5종의 바이러스를 60℃, 37℃, 4℃에서 시간별 생존력을 조사하였다. HEp2 cell을 이용한 plaque assay를 통해 샘플 내 live virus titer 분석을 진행하였다. 분석 결과, 모든 온도 조건에서 wild type에 비하여 변이 바이러스의 안정성이 증가되었음을 확인하였다. RSV 바이러스의 특성상 분리된 바이러스의 안정성이 매우 떨어지는데, 도 9의 결과에서 확인할 수 있듯이, 재조합된 RSV 바이러스는 야생형에 비해 고온, 사람의 체온, 그리고 저온에서도 야생형 바이러스주에 비해 안정성이 우수하다.
9.
면역원성 시험
Mock, wtRSVA, cRSVA_MVF_S, cRSVA_NDVF_S, cRSVA_MVF_A, 및 cRSVA_NDVF_A를 마우스 IM에 1x105 pfu/mouse 농도로 2회 면역하였다. 2주 후에 각 마우스의 혈청을 분리하고 ELISA를 통해 총항체가 및 plaque reduction neutralization test를 통해 중화항체를 측정하였다. 그 결과는 도 10에 나타냈다. Mock를 제외한 모든 그룹에서 RSV 항원에 특이적 IgG 항체와 virus 감염을 중화하는 항체가 충분히 형성되었음이 확인되었다. Mock는 G1으로, WtRSVA는 G2로, cRSVA_MVF_S는 G3으로, cRSVA_NDVF_S는 G4로, cRSVA_MVF_A는 G5로, cRSVA_NDVF_A는 G6로, 그리고 FIwtRSVA는 G7으로 나타냈다. 재조합된 RSV 바이러스주들은 RSV 야생형과 비슷한 수준의 항체를 생성하였고, 불활화된 G7에 비해서는 항체 생성율이 훨씬더 우수하다는 것을 알 수 있다. 도 10의 결과를 통해 재조합된 RSV 바이러스주들은 야생형 바이러스 수준으로 항체를 생성하면서도, 안정성이 우수하여 뛰어난 바이러스주로 이용될 수 있음을 확인하였다.
10.
면역 효력 시험
5종의 바이러스를 마우스의 IM에 105pfu/mouse 농도로 2주 간격 2회 접종하였다. 면역 후 2주 후 야생형 RSV를 2x106pfu/mouse 의 농도로 마우스 비강에 challenge하였다. 1~12일차 blood에서 viremia를 q-PCR을 통해 검출하고, body weight 변화를 측정하였다. 그 결과는 도 11에 나타냈다. 모든 면역 그룹에서 바이러스 감염을 효과적으로 억제함을 확인하였다. 특히 야생형 바이러스주와 비슷한 수준으로 감염이 억제되는 것을 알 수 있었으며, 불활화 바이러스주에 비해서는 혈액 내 바이러스 감염 정도가 현저히 적었음을 알 수 있다.
11. MV와
NDV
에 대한 면역원성 시험
상기 9. 항목의 실험 방법과 유사하게, 동일 혈청을 이용하여 NDV와 MV 항원에 대한 총항체가와 중화항체가를 측정하였다. 총항체가 측정을 위해 MV와 DNV 항원을 각각 coating 하여 ELISA를 수행하였다. 중화항체 측정을 위해, MV와 NDV 의 감염을 각각 억제하는 농도를 plaque inhibition assay로 측정하였다. 그 결과, 도 12 및 도 13에서처럼 MV와 NDV의 F 항원을 가지는 그룹에서만 각각의 항원에 특이적인 항체와 바이러스 중화항체가 충분히 형성되었음이 확인 되었다. 그러나, 이종의 F 가 삽입되지 않는 그룹은 각 항원에 특히 항체가 형성되지 않았으며 중화항체도 유도되지 않았다.
<110> SK bioscience Co., Ltd.
<120> Recombinant RSV live vaccine strain and the preparing method
thereof
<130> P19-213
<150> KR 10-2018-0122162
<151> 2018-10-12
<160> 11
<170> KoPatentIn 3.0
<210> 1
<211> 15232
<212> DNA
<213> respiratory syncytial virus
<400> 1
aaacttgcgt aaaccaaaaa aatggggcaa ataagaattt gataagtacc acttaaattt 60
aactcctttg gttagagatg ggcagcaact cattgagtat gataaaagtt agattgcaaa 120
atctgtttga caatgatgaa gtagcattgt taaaaataac atgctatact gacaaattaa 180
tacagttaac taatgctttg gctaaggcag ttatacatac aatcaaattg aatggcattg 240
tatttgtgca tgttattaca agtagtgata tttgccctaa taataatatt gtagtgaaat 300
ccaatttcac aacaatgcca gtattacaaa atggaggtta tatatgggaa atgatggaat 360
taacacactg ctctcaacct aatggcctaa tagatgacaa ttgtgaaatt aaattctcca 420
aaaaactaag tgattcaaca atgaccaatt atatgaatca attatctgaa ttacttggat 480
ttgacctcaa tccataaatc ataataaata tcaactagca aatcaatgtc actaacacca 540
ttagttaata taaaacttga cagaagataa aaatggggca aataaatcaa ttcagccgac 600
ccaaccatgg acacaacaca caatgatacc acaccacaaa gactgatgat cacagacatg 660
aggccattat cgcttgagac tataataaca tctctaacca gagatatcat aacacataaa 720
tttatatact tgataaatca tgaatgcata gtaagaaaac ttgatgaaag acaggccaca 780
tttacatttc tggtcaacta tgaaatgaaa ctattgcaca aagtgggaag cactaaatat 840
aaaaaatata ctgaatacaa cacaaaatat ggcactttcc ctatgccaat atttatcaat 900
catgatgggt tcttagaatg cattggcatt aagcctacca agcacacacc cataatatac 960
aagtatgatc tcaatccatg aatatcaaac caagattcaa acaatccgaa ataacaactt 1020
tatgcataat cacactccat agtccaaatg gagcctgaaa attatagtta tttaaaatta 1080
aggagagaca taagatgaaa gatggggcaa atacaaaaat ggctcttagc aaagtcaagt 1140
tgaatgatac actcaacaaa gatcaacttc tatcatccag caaatatacc atccaacgga 1200
gcacaggaga cagcattgac actcctaatt atgatgtgca gaaacacatt aataagttat 1260
gtggcatgtt attaatcaca gaagatgcta atcataaatt cactgggtta ataggtatgt 1320
tatatgctat gtctagatta ggaagagaag acaccataaa aatactcaaa gatgcgggat 1380
atcatgttaa ggcaaatgga gtggatgtaa caacacatcg tcaagacatt aatgggaaag 1440
aaatgaaatt tgaagtgtta acattagcaa gcttaacaac tgaaattcaa atcaacattg 1500
agatagaatc tagaaaatcc tacaaaaaaa tgctaaaaga aatgggagag gtggctccag 1560
aatacaggca tgactctcct gattgtggga tgataatatt atgtatagcg gcattagtaa 1620
taaccaaatt agcagcagga gatagatcag gtcttacagc tgtgattagg agagctaata 1680
atgtcctaaa aaatgaaatg aaacgttata aaggtttatt acccaaggat atagccaaca 1740
gcttctatga agtgtttgaa aaatatcctc actttataga tgtttttgtt cattttggta 1800
tagcacaatc ttctaccaga ggtggcagta gagttgaagg gatttttgca ggattgttta 1860
tgaatgccta tggtgcaggg caagtgatgt tacggtgggg ggtcttagca aaatcagtta 1920
aaaacattat gttaggacac gctagtgtac aagcagaaat ggaacaagtt gtggaggtgt 1980
atgagtatgc tcagaaattg ggtggagaag caggattcta ccatatattg aacaacccaa 2040
aagcatcact attatctttg actcaatttc ctcacttctc tagtgtagta ttgggcaatg 2100
ctgctggcct aggcataatg ggagaataca gaggtacacc aaggaatcaa gatttatatg 2160
atgctgcaaa agcatatgct gaacaactca aagaaaatgg tgtgattaac tacagtgtat 2220
tagatttgac agcagaagaa ctagaggcta tcaaacatca gcttaatcca aaagataatg 2280
atgtagagct ttgagttaat aaaaaagtgg ggcaaataaa tcatcatgga aaagtttgct 2340
cctgaattcc atggagaaga tgcaaacaac agagccacca aattcctaga atcaataaag 2400
ggcaaattca catcacccaa agatcccaag aaaaaagata gtatcatatc tgtcaactca 2460
atagatatag aagtaaccaa agaaagccct ataacatcaa attcaaccat tataaaccca 2520
ataaatgaga cagatgatac tgtagggaac aagcccaatt atcaaagaaa gcctctagta 2580
agtttcaaag aagaccctac gccaagtgat aatccttttt caaaactata caaagaaacc 2640
atagaaacat ttgataacaa tgaagaagaa tctagctatt catatgaaga aataaatgat 2700
cagacaaacg ataatataac agcaagatta gataggattg atgagaaatt aagtgaaata 2760
ctaggaatgc ttcacacatt agtagtagcg agtgcaggac ccacatctgc tcgggatggt 2820
ataagagatg ccatggttgg tttaagagaa gaaatgatag aaaaaatcag aactgaagca 2880
ttaatgacca atgacagact agaagctatg gcaagactca ggaatgaaga aagtgaaaag 2940
atggcaaaag acacatcaga tgaagtgtct ctcaatccaa catcagagaa actgaacaac 3000
ctgttggaag ggaatgatag tgacaatgat ctatcacttg aagatttctg attagctacc 3060
aaactgtaca tcaaaacaca acaccaatag aaaaccaaca aacaaaccaa ctcacccatc 3120
caaccaaaca tctatctgct gattagccaa ccagccaaaa aacaaccagc caatctaaaa 3180
ctagccaccc ggaaaaaatc gatactatag ttacaaaaaa agatggggca aatatggaaa 3240
catacgtgaa taaacttcac gagggctcca catacacagc tgctgttcaa tacaatgtcc 3300
tagaaaaaga cgatgatcct gcatcactta caatatgggt gcccatgttc caatcatcca 3360
tgccagcaga tctactcata aaagaactag ccaatgtcaa tatactagtg aaacaaatat 3420
ccacacccaa gggaccctca ttaagagtca tgataaactc aagaagtgca gtgctagcac 3480
aaatgcccag caaatttacc atatgtgcca atgtgtcctt ggatgaaaga agcaagctgg 3540
catatgatgt aaccacaccc tgtgaaatta aggcatgcag tctaacatgc ctaaaatcaa 3600
aaaatatgtt aactacagtt aaagatctca ctatgaaaac actcaaccca acacatgaca 3660
tcattgcttt atgtgaattt gaaaatatag taacatcaaa aaaagtcata ataccaacat 3720
acctaagatc tatcagcgtc agaaataaag atctgaacac acttgaaaat ataacaacca 3780
ctgaattcaa aaatgccatt acaaatgcaa aaatcatccc ttactcagga ttattgttag 3840
tcatcacagt gactgacaac aaaggagcat tcaaatacat aaagccacaa agtcaattca 3900
tagtagatct tggagcttac ctagaaaaag aaagtatata ttatgttaca acaaattgga 3960
agcacacagc tacacgattt gcaatcaaac ccatggaaga ttaacctttt tcctctacat 4020
caatgagtag attcatacaa actttctaac tacattcttc acttcacaat cataatcacc 4080
aaccctctgt ggttcaatca atcaaacaaa actcatcaag agttccagat catcccaagt 4140
cattgttcat cagatccagt actcaaataa gttaataaaa aatccacatg gggcaaataa 4200
tcattgaggg aaatccaact aatcacaaca tctgtcaaca tagacaagtc aacacgctag 4260
ataaaatcaa ccaatggaaa atacatccat aactatagaa ttctcaagca aattctggcc 4320
ttactttaca ctaatacaca tgataacaac aataatctct ttgataatca taatctccat 4380
catgattgca atactaaaca aactctgcga atataatgta ttccataaca aaacctttga 4440
gctaccaaga gctcgagtca atacatagca ttcaccaatc tgatagctca aaacagtaac 4500
cttgcatttg taaatgaact accctcactt cttcacaaaa ccacatcaac atctcaccat 4560
gcaagccatc atctatacca taaagtagtt aattaaaaat agtcataaca atgaactagg 4620
atattaagac caaaaacaac gctggggcaa atgcaaacat gtccaaaacc gaggaccaac 4680
gcaccgccaa gacactagaa aggacctggg acacttttaa tcatctatta ttcatatcat 4740
cgtgcttata caagttaaat cttaaatcta tagcacaaat cacattatct attttggcaa 4800
tgataatctc aacctcactt ataattgcag ccatcatatt catagcctcg gcaaaccaca 4860
aagtcacact aacaactgca atcatacaag atgcaacgaa ccagatcaag aacacaaccc 4920
caacatacct cacccagaat ccccagcatg gaatcagctt ctccaatctg tccggaacta 4980
catcacaatc caccaccata ctagcttcaa caacaccaag tgctgattca accccacaat 5040
ccacaacagt caagatcaaa aacacaacaa caacccaaat attacctagc aaacccacca 5100
caaaacaacg ccaaaataaa ccacaaaaca aacccaacaa tgattttcac tttgaagtgt 5160
tcaattttgt accctgcagc atatgcagca acaatccaac ctgctgggcc atctgcaaga 5220
gaataccaaa caaaaaacct ggaaagaaaa ccaccaccaa gcccacaaaa aaaccaaccc 5280
tcaagacaac caaaaaagat cccaaatccc aaaccacaaa accaaaggaa gtactcacta 5340
ccaagcctac aggaaagcca accatcaaca ccactaaaac aaacatcaga actacactgc 5400
tcacctccaa caccaaagga aatccagaac acacaagtca agaggaaacc ctccactcaa 5460
ccacctccga aggctatcca agcccatcac aagtccacac aacatccggt caagaggaaa 5520
ccctccactc aaccacctcc gaaggctatc caagcccatc acaagtctac acaacatccg 5580
agtacctatc acaatctcta tcttcatcca acacaacaaa atgatagtca ttaaaaagcg 5640
tattgttgca aaaagccatg accaaatcaa acagaatcaa aatcaactct ggggcaaata 5700
acaatggagt tgccaatcct caaaacaaat gctattacca caatccttgc tgcagtcaca 5760
ctctgtttcg cttccagtca aaacatcact gaagaatttt atcaatcaac atgcagtgca 5820
gtcagcaaag gctatcttag tgctctaaga actggttggt atactagtgt tataactata 5880
gaattaagta atatcaagga aaataagtgt aatggtacag acgctaaggt aaaattaata 5940
aaacaagaat tagataaata taaaaatgct gtaacagaat tgcagttgct catgcaaagc 6000
acaccagcag ccaacaatcg agccagaaga gaactaccaa gatttatgaa ttatacactc 6060
aacaatacca aaaacaccaa tgtaacatta agtaagaaaa ggaaaagaag atttcttgga 6120
tttttgttag gtgttggatc tgcaatcgcc agtggcattg ccgtatccaa ggtcctgcac 6180
ctagaagggg aagtgaacaa aatcaaaagt gctctactat ccacaaacaa ggctgtagtc 6240
agcttatcta atggagtcag tgtcttaacc agcaaggtgt tagacctcaa aaactatata 6300
gataaacagt tgttacctat tgttaacaag caaagctgca gcatatcaaa cattgaaact 6360
gtgatagagt tccaacaaaa gaacaacaga ctactagaga ttaccagaga atttagtgtt 6420
aatgcaggtg taactactcc tgtaagcact tatatgttaa ctaatagtga gttattatca 6480
ttaatcaatg atatgcctat aacaaatgat cagaaaaagt taatgtccag caatgttcaa 6540
atagttagac agcaaagtta ctctatcatg tcaataataa aagaggaagt cttggcatat 6600
gtagtacaat taccactata tggtgtaata gatactcctt gttggaaact acacacatcc 6660
cctttatgta caaccaacac aaaggaagga tccaacatct gcttaacaag aaccgacaga 6720
ggatggtact gtgacaatgc aggatcagta tcctttttcc cacaagctga aacatgtaaa 6780
gttcaatcga atcgggtgtt ttgtgacaca atgaacagtt taacattacc aagtgaggta 6840
aatctctgca acattgacat attcaacccc aaatatgatt gcaaaattat gacttcaaaa 6900
acagatgtaa gcagctccgt tatcacatct ctaggagcca ttgtgtcatg ctatggcaaa 6960
accaaatgta cagcatccaa taaaaatcgt gggatcataa agacattctc taacgggtgt 7020
gattatgtat caaataaggg ggtggatact gtgtctgtag gtaatacatt atattatgta 7080
aataagcaag aaggcaaaag tctctatgta aaaggtgaac caataataaa tttctatgat 7140
ccattagtgt tcccctctga tgaatttgat gcatcaatat ctcaagtcaa tgagaaaatt 7200
aatcagagtc tagcatttat ccgtaaatca gatgaattat tacataatgt aaatgctggt 7260
aaatccacca caaatatcat gataactacc ataattatag taattatagt aatattgtta 7320
gcattaattg cagttggact gcttctatac tgcaaggcca gaagcacacc agtcacatta 7380
agtaaggatc aactgagtgg tataaataat attgcattta gtaactgaat aaaaatagca 7440
cctaatcata ttcttacaat ggttcgctat ttgaccatag ataacccatc tatcattaga 7500
ttatcctaaa atttgaactt catcacaact ttcatctata aaccatctca cttacacttt 7560
ttaagtagat ttctatttta tagttatata aaacaattga ataccaaatt aacttactat 7620
ttgtaaaaat gagaattggg gcaaatatgt cacgaaggaa tccttgcaaa ttcgaaattc 7680
gaggtcattg cttgaatggt aaaaggtgtc attttagtca taattatttt gaatggccac 7740
cccatgcact gcttgtaaga caaaacttta tgttaaacag aatacttaag tctatggata 7800
aaagcataga tactttgtca gaaataagtg gagctgcaga gttggacaga acagaagagt 7860
atgccctcgg tgtagttgga gtgctagaga gttatatagg atcaataaat aatataacta 7920
aacaatcagc atgtgttgcc atgagcaaac tccttactga actcaacagc gatgacatca 7980
aaaaactaag ggacaatgaa gagccaaact cacccaaagt aagagtgtac aatactgtca 8040
tatcatatat tgaaagcaac aggaagaaca ataaacaaac tatccatctg ttaaaaagat 8100
tgccagcaga cgtattgaag aaaaccatca aaaacacatt ggatatccac aagagcataa 8160
ccatcaataa cccaaaagaa tcaactgtta gtgatacgaa cgaccatgcc aaaaataatg 8220
atactacctg acaaatatcc ttgtagtata aattccatac taataacaag taattgtaga 8280
gtcactatgt ataatcaaaa aaacacacta tatatcaatc aaaacaacca aaatagccat 8340
atatacccac cggatcaacc attcaatgaa atccattgga cctctcaaga cttgattgat 8400
gcaactcaaa attttctaca acatctaggt attactgatg atatatacac aatatatata 8460
ttagtgtcat aatactcaat cctaatactt accacatcat caaattatta actcaaacaa 8520
ttcaagctat gggacaaaat ggatcccatt attagtggaa attctgctaa tgtttatcta 8580
actgatagtt atttaaaagg tgttatttct ttctcagaat gtaacgcttt aggaagttac 8640
atattcaatg gtccttatct caaaaatgat tataccaact taattagtag acaaaatcca 8700
ttaatagaac acataaatct aaagaaacta aatataacac agtccttaat atctaagtat 8760
cataaaggtg aaataaaaat agaagaacct acttactttc agtcattact tatgacatac 8820
aagagtatga cctcttcaga acagactact actactaatt tacttaaaaa gataataaga 8880
agagctatag aaatcagtga tgtcaaagtc tatgctatat tgaataaact ggggctcaaa 8940
gaaaaagaca agattaaatc caataatgga caagatgaag acaactcagt cattactacc 9000
ataatcaaag atgatatact tttagctgtc aaggataatc aatctcatct taaagcagac 9060
aaaaatcaat ccacaaaaca aaaagataca atcaaaacaa cacttttgaa gaaattaatg 9120
tgttcgatgc aacatcctcc atcatggtta atacattggt ttaatttata cacaaaatta 9180
aacagcatat taacacaata tcgatctagt gaggtaaaaa accatggttt tatattgata 9240
gataatcata ctcttagtgg attccaattt attttgaatc aatatggttg tatagtttat 9300
cataaggaac tcaaaagaat tactgtgaca acttataatc aattcttgac atggaaagat 9360
attagcctta gtagattaaa tgtttgtttg attacatgga ttagtaactg tttgaacaca 9420
ttaaacaaaa gcttaggctt aagatgtgga ttcaataatg ttatcttgac acaattattc 9480
ctttatggag attgtatact aaaactattc cacaatgagg ggttctacat aataaaagag 9540
gtagagggat ttattatgtc tctaatttta aatataacag aagaagatca attcagaaaa 9600
cggttttata atagtatgct caacaacatc acagatgccg ccaacaaagc tcaaaaaaat 9660
ctgctatcaa gagtatgtca tacattatta gataagacaa tatcagataa tataataaat 9720
ggcagatgga taattctatt gagtaagttc ctaaaattaa ttaagcttgc aggtgacaat 9780
aacctcaaca atctgagtga attatatttt ttgttcagaa tatttggaca cccaatggta 9840
gatgaaagac aagccatgga tgctgttaaa gttaattgca acgagaccaa attttatttg 9900
ttaagtagtt tgagtatgtt aagaggagct tttatatata gaattataaa agggtttgta 9960
aataattaca acagatggcc tactttaaga aatgccattg tcttaccctt aagatggtta 10020
acttactata aactaaacac ttatccttcc ttgttggaac ttacagaaag agatttgatt 10080
gttctatcag gactacgttt ctatcgagag tttcggttgc ctaaaaaagt ggatcttgaa 10140
atgatcataa atgataaggc tatatcacct cctaaaaatt taatatggac tagtttccct 10200
agaaattata tgccgtcaca catacaaaat tatatagaac atgaaaaatt aaaattctct 10260
gatagtgata aatcaagaag agtattagag tattatttaa gagataacaa attcaatgaa 10320
tgtgatttac acaactgtgt agttaatcaa agttatctta acaacccgaa tcatgtggta 10380
tcattgacag gcaaagaaag agaactcagt gtaggtagaa tgtttgcaat gcaaccagga 10440
atgttcagac aagttcaaat attagcagag aaaatgatag cagaaaacat attacaattt 10500
ttccctgaaa gtcttacaag atatggtgat ctagaactac agaaaatatt agaattgaaa 10560
gcaggaataa gtaacaaatc aaatcgttac aatgataatt acaacaatta cattagtaag 10620
tgctctatca tcacagatct cagcaaattc aatcaagcat ttcgatatga aacatcatgt 10680
atttgtagtg atgtactgga tgaactgcat ggtgtacaat ctctattttc ctggttacat 10740
ttaactattc ctcatgtcac aataatatgc acatataggc atgcaccccc ctatataaag 10800
gatcatattg tagatcttaa caatgtagat gagcaaagtg gactatatag atatcatatg 10860
ggtggtatcg aagggtggtg tcaaaaacta tggaccatag aagctatatc actattagat 10920
ctaatatctc tcaaagggaa attctcaatt actgctttaa ttaatggtga caatcaatca 10980
atagatataa gtaaaccagt cagactcatg gaaggtcaaa ctcatgctca agcagattat 11040
ttgctagcat taaatagtct caaattactg tataaagagt atgcaggaat aggccacaaa 11100
ttaaaaggaa ctgagactta tatatcgaga gatatgcaat ttatgagtaa aacgatccaa 11160
cataacggtg tatattaccc agctagtata aagaaagtcc taagagtggg accgtggata 11220
aacactatac ttgatgactt caaagtgagt ctagaatcta taggtagttt gacacaagaa 11280
ttagaatata gaggtgaaag tctattatgc agtttaatat ttagaaatgt atggttatat 11340
aatcaaattg cattacaact taaaaatcat gcattatgta acaacaaatt atatttggat 11400
atattaaaag ttctaaaaca cttaaaaacc ttttttaatc ttgataacat tgatacagca 11460
ttaacattgt atatgaattt gcccatgtta tttggtggtg gtgatcccaa cttgttatat 11520
cgaagtttct atagaagaac tcctgatttc ctcacagagg ctatagttca ctctgtgttc 11580
atacttagtt attatacaaa ccatgattta aaagataaac ttcaagatct gtcagatgat 11640
agattgaata agttcttaac atgcataatc acgtttgata aaaaccccaa tgctgaattc 11700
gttacattga tgagagatcc tcaagcttta ggatctgaga ggcaagctaa aattactagc 11760
gaaatcaata gactggcagt taccgaggtt ttgagcacag ctccaaacaa aatattttcc 11820
aaaagtgcac aacactatac cactacagag atagatctta atgatattat gcaaaatata 11880
gaacctacat atcctcacgg gctaagagtt gtttatgaga gtttaccctt ttataaagca 11940
gagaaaatag taaatcttat atccggtaca aaatctataa ctaacatact ggaaaagact 12000
tctgccatag acttaacaga tattgataga gccactgaga tgatgaggaa aaacataact 12060
ttgcttataa ggatattacc attagattgt aacagagata aaagagaaat attgagtatg 12120
gaaaacctaa gtattactga attaagcaaa tacgttagag aaagatcttg gtctttatcc 12180
aatatagttg gtgttacatc acccagtatc atgtatacaa tggacataaa atatacaaca 12240
agcactatag ctagtggcat aatcatagag aaatataatg tcaacagttt aacacgtggt 12300
gagagaggac ccactaaacc atgggttggt tcatctacac aagagaaaaa gacaatgcca 12360
gtttataata gacaagtttt aaccaaaaaa cagagagatc aaatagatct attagcaaaa 12420
ttggattggg tgtatgcatc tatagataac aaggatgaat ttatggagga acttagcata 12480
ggaactcttg ggttaacata tgagaaggcc aaaaaattat tcccacaata tttgagtgtt 12540
aactatttgc atcgtcttac agtcagtagt agaccatgtg aattccctgc atctatacca 12600
gcttatagaa ctacaaatta tcactttgat actagcccta ttaatcgcat attaacagaa 12660
aagtatggtg atgaagatat tgatatagta ttccaaaact gtataagctt tggccttagc 12720
ttaatgtctg tagtagaaca atttactaat gtatgtccta acagaattat tctcataccc 12780
aagcttaatg agatacattt gatgaaacct cccatattca caggcgatgt tgatattcac 12840
aagttaaaac aagtgataca aaaacaacat atgtttttac cagacaaaat aagtttgact 12900
caatatgtgg aattattctt aagtaataaa acactcaaat ctggatctaa tgttaattct 12960
aatttaatat tggcgcataa gatatctgac tattttcata atacttacat tttgagtact 13020
aatttagctg gacattggat tcttattata caacttatga aagattctaa gggtattttt 13080
gaaaaagatt ggggagaggg atatataact gatcatatgt tcattaattt gaaagttttc 13140
ttcaatgctt ataagacata tctcttgtgt tttcataaag gttacggcag agcaaagctg 13200
gagtgtgata tgaatacttc agatctccta tgtgtattgg aattaataga cagtagttat 13260
tggaagtcta tgtctaaggt gtttttagaa caaaaagtta tcaaatacat tcttagccag 13320
gatgcaagtt tacatagagt aaaaggatgt catagcttca aactatggtt tcttaaacgt 13380
cttaatgtag cagaattcac agtttgccct tgggttgtta acatagatta tcatccaaca 13440
catatgaaag caatattaac ttatattgat cttgttagaa tgggattgat aaatatagat 13500
agaatataca ttaaaaataa acacaagttc aatgatgagt tttatacttc taatctgttt 13560
tacattaatt ataacttctc agataatact catctattaa ctaaacatat aaggattgct 13620
aattccgaat tagaaagtaa ttacaacaaa ttatatcatc ctacaccaga aaccctagaa 13680
aatatactaa ccaatccggt taaaagtaat gagaaaaaga cactgagtga ctattgtata 13740
ggtaaaaatg ttgactcaat aatgttacca tcgttatcta ataagaagct tattaaatcg 13800
tctacaatga ttagaaccaa ttacagcaga caagatttgt ataatttatt tcctacggtt 13860
gtgattgata aaattataga tcattcaggt aatacagcca aatctaacca actttacact 13920
actacttctc atcaaatatc cttagtgcac aatagcacat cactttattg catgcttcct 13980
tggcatcata ttaatagatt caattttgta tttagttcta caggttgtaa aattagtata 14040
gagtatattt taaaagatct taaaattaag gatcctaatt gtatagcatt cataggtgaa 14100
ggagcaggga atttattatt gcgtacagta gtggaacttc atcctgatat aagatatatt 14160
tacagaagtc tgaaagattg caatgatcat agtttaccaa ttgagttttt aaggctgtac 14220
aatggacata tcaacattga ttatggtgaa aatttgacca ttcctgctac agatgcaacc 14280
aacaacattc attggtctta tttacatata aagtttgctg aacctatcag tctttttgtc 14340
tgtgatgctg aattgcctgt aacagtcaac tggagtaaga ttataataga gtggagcaag 14400
catgtaagaa aatgcaagta ctgttcttca gttaataaat gtacattgat agtaaaatat 14460
catgctcaag atgatatcga tttcaaatta gacaacataa ctatattaaa aacttatgta 14520
tgcttaggta gtaagttaaa gggatctgaa gtttacttag tccttacaat aggtcctgca 14580
aatgtgttcc cagtatttaa tgtagtacaa aatgctaaat tgatactatc aagaactaaa 14640
aatttcatca tgcctaaaaa agctgataaa gagtctattg atgcaaatat taagagtttg 14700
ataccctttc tttgttaccc tataacaaaa aaaggaatta atactgcatt gtctaaatta 14760
aagagtgttg ttagtggaga tatactatca tattctatag ctggacgtaa tgaagttttc 14820
agcaataaac ttataaatca taagcatatg aacatcttaa agtggttcaa tcatgtttta 14880
aatttcagat caacagaatt aaactataat catttatata tggtagaatc tacttatcct 14940
catctaagtg aattgttaaa cagcttgaca accaatgaac ttaaaaaact gattaaaatc 15000
acaggtagtt tgttatacaa cttttataat gaataatgag caaaaatctt ataacaaaaa 15060
tagctacaca ctaacattgt attcaattat agttattgaa aattaataat tatataattt 15120
ttaataactt ctagtgaact aatcctaaaa ttatcatttt gatctaggaa gaataagttt 15180
aaatccaaat ctaattggtt tatatgtata ttaactaaat tacgagatat ta 15232
<210> 2
<211> 15311
<212> DNA
<213> respiratory syncytial virus
<400> 2
acgcgaaaaa atgcgtacaa caaacttgcg taaaccaaaa aaatggggca aataagaatt 60
tgataagtac cacttaaatt taactccttt ggttagaggc gcgccatggg cagcaactca 120
ttgagtatga taaaagttag attgcaaaat ctgtttgaca atgatgaagt agcattgtta 180
aaaataacat gctatactga caaattaata cagttaacta atgctttggc taaggcagtt 240
atacatacaa tcaaattgaa tggcattgta tttgtgcatg ttattacaag tagtgatatt 300
tgccctaata ataatattgt agtgaaatcc aatttcacaa caatgccagt attacaaaat 360
ggaggttata tatgggaaat gatggaatta acacactgct ctcaacctaa tggcctaata 420
gatgacaatt gtgaaattaa attctccaaa aaactaagtg attcaacaat gaccaattat 480
atgaatcaat tatctgaatt acttggattt gacctcaatc cataaatcat aataaatatc 540
aactagcaaa tcaatgtcac taacaccatt agttaatata aaacttgaca gaagataaaa 600
atggggcaaa taaatcaatt cagccgaccc aaccatggac acaacacaca atgataccac 660
accacaaaga ctgatgatca cagacatgag gccattatcg cttgagacta taataacatc 720
tctaaccaga gatatcataa cacataaatt tatatacttg ataaatcatg aatgcatagt 780
aagaaaactt gatgaaagac aggccacatt tacatttctg gtcaactatg aaatgaaact 840
attgcacaaa gtgggaagca ctaaatataa aaaatatact gaatacaaca caaaatatgg 900
cactttccct atgccaatat ttatcaatca tgatgggttc ttagaatgca ttggcattaa 960
gcctaccaag cacacaccca taatatacaa gtatgatctc aatccatgaa tatcaaacca 1020
agattcaaac aatccgaaat aacaacttta tgcataatca cactccatag tccaaatgga 1080
gcctgaaaat tatagttatt taaaattcct gcaggaagga gagacataag atgaaagatg 1140
gggcaaatac aaaaatggct cttagcaaag tcaagttgaa tgatacactc aacaaagatc 1200
aacttctatc atccagcaaa tataccatcc aacggagcac aggagacagc attgacactc 1260
ctaattatga tgtgcagaaa cacattaata agttatgtgg catgttatta atcacagaag 1320
atgctaatca taaattcact gggttaatag gtatgttata tgctatgtct agattaggaa 1380
gagaagacac cataaaaata ctcaaagatg cgggatatca tgttaaggca aatggagtgg 1440
atgtaacaac acatcgtcaa gacattaatg ggaaagaaat gaaatttgaa gtgttaacat 1500
tagcaagctt aacaactgaa attcaaatca acattgagat agaatctaga aaatcctaca 1560
aaaaaatgct aaaagaaatg ggagaggtgg ctccagaata caggcatgac tctcctgatt 1620
gtgggatgat aatattatgt atagcggcat tagtaataac caaattagca gcaggagata 1680
gatcaggtct tacagctgtg attaggagag ctaataatgt cctaaaaaat gaaatgaaac 1740
gttataaagg tttattaccc aaggatatag ccaacagctt ctatgaagtg tttgaaaaat 1800
atcctcactt tatagatgtt tttgttcatt ttggtatagc acaatcttct accagaggtg 1860
gcagtagagt tgaagggatt tttgcaggat tgtttatgaa tgcctatggt gcagggcaag 1920
tgatgttacg gtggggggtc ttagcaaaat cagttaaaaa cattatgtta ggacacgcta 1980
gtgtacaagc agaaatggaa caagttgtgg aggtgtatga gtatgctcag aaattgggtg 2040
gagaagcagg attctaccat atattgaaca acccaaaagc atcactatta tctttgactc 2100
aatttcctca cttctctagt gtagtattgg gcaatgctgc tggcctaggc ataatgggag 2160
aatacagagg tacaccaagg aatcaagatt tatatgatgc tgcaaaagca tatgctgaac 2220
aactcaaaga aaatggtgtg attaactaca gtgtattaga tttgacagca gaagaactag 2280
aggctatcaa acatcagctt aatccaaaag ataatgatgt agagctttga gttaataaaa 2340
aagtggggca aataaatcat catggaaaag tttgctcctg aattccatgg agaagatgca 2400
aacaacagag ccaccaaatt cctagaatca ataaagggca aattcacatc acccaaagat 2460
cccaagaaaa aagatagtat catatctgtc aactcaatag atatagaagt aaccaaagaa 2520
agccctataa catcaaattc aaccattata aacccaataa atgagacaga tgatactgta 2580
gggaacaagc ccaattatca aagaaagcct ctagtaagtt tcaaagaaga ccctacgcca 2640
agtgataatc ctttttcaaa actatacaaa gaaaccatag aaacatttga taacaatgaa 2700
gaagaatcta gctattcata tgaagaaata aatgatcaga caaacgataa tataacagca 2760
agattagata ggattgatga gaaattaagt gaaatactag gaatgcttca cacattagta 2820
gtagcgagtg caggacccac atctgctcgg gatggtataa gagatgccat ggttggttta 2880
agagaagaaa tgatagaaaa aatcagaact gaagcattaa tgaccaatga cagactagaa 2940
gctatggcaa gactcaggaa tgaagaaagt gaaaagatgg caaaagacac atcagatgaa 3000
gtgtctctca atccaacatc agagaaactg aacaacctgt tggaagggaa tgatagtgac 3060
aatgatctat cacttgaaga tttctgatta gctaccaaac tgtacatcaa aacacaacac 3120
caatagaaaa ccaacaaaca aaccaactca cccatccaac caaacatcta tctgctgatt 3180
agccaaccag ccaaaaaaca accagccaat ctaaaactag ccacccggaa aaaatcgata 3240
ctatagttac aaaaaaagat ggggcaaata tggaaacata cgtgaataaa cttcacgagg 3300
gctccacata cacagctgct gttcaataca atgtcctaga aaaagacgat gatcctgcat 3360
cacttacaat atgggtgccc atgttccaat catccatgcc agcagatcta ctcataaaag 3420
aactagccaa tgtcaatata ctagtgaaac aaatatccac acccaaggga ccctcattaa 3480
gagtcatgat aaactcaaga agtgcagtgc tagcacaaat gcccagcaaa tttaccatat 3540
gtgccaatgt gtccttggat gaaagaagca agctggcata tgatgtaacc acaccctgtg 3600
aaattaaggc atgcagtcta acatgcctaa aatcaaaaaa tatgttaact acagttaaag 3660
atctcactat gaaaacactc aacccaacac atgacatcat tgctttatgt gaatttgaaa 3720
atatagtaac atcaaaaaaa gtcataatac caacatacct aagatctatc agcgtcagaa 3780
ataaagatct gaacacactt gaaaatataa caaccactga attcaaaaat gccattacaa 3840
atgcaaaaat catcccttac tcaggattat tgttagtcat cacagtgact gacaacaaag 3900
gagcattcaa atacataaag ccacaaagtc aattcatagt agatcttgga gcttacctag 3960
aaaaagaaag tatatattat gttacaacaa attggaagca cacagctaca cgatttgcaa 4020
tcaaacccat ggaagattaa cctttttcct ctacatcaat gagtagattc atacaaactt 4080
tctaactaca ttcttcactt cacaatcata atcaccaacc ctctgtggtt caatcaatca 4140
aacaaaactc atcaagagtt ccagatcatc ccaagtcatt gttcatcaga tccagtactc 4200
aaataagtta ataaaaaatc cacatggggc aaataatcat tgagggaaat ccaactaatc 4260
acaacatctg tcaacataga caagtcaaca cgctagataa aatcaaccaa tggaaaatac 4320
atccataact atagaattct caagcaaatt ctggccttac tttacactaa tacacatgat 4380
aacaacaata atctctttga taatcataat ctccatcatg attgcaatac taaacaaact 4440
ctgcgaatat aatgtattcc ataacaaaac ctttgagcta ccaagagctc gagtcaatac 4500
atagcattca ccaatctgat agctcaaaac agtaaccttg catttgtaaa tgaactaccc 4560
tcacttcttc acaaaaccac atcaacatct caccatgcaa gccatcatct ataccataaa 4620
gtagttaatt aaaaatggcc ggccagtcat aacaatgaac taggatatta agaccaaaaa 4680
caacgctggg gcaaatgcaa acatgtccaa aaccgaggac caacgcaccg ccaagacact 4740
agaaaggacc tgggacactt ttaatcatct attattcata tcatcgtgct tatacaagtt 4800
aaatcttaaa tctatagcac aaatcacatt atctattttg gcaattataa tctcaacctc 4860
acttataatt gcagccatca tattcatagc ctcggcaaac cacaaagtca cactaacaac 4920
tgcaatcata caagatgcaa cgaaccagat caagaacaca accccaacat acctcaccca 4980
gaatccccag catggaatca gcttctccaa tctgtccgga actacatcac aatccaccac 5040
catactagct tcaacaacac caagtgctga ttcaacccca caatccacaa cagtcaagat 5100
caaaaacaca acaacaaccc aaatattacc tagcaaaccc accacaaaac aacgccaaaa 5160
taaaccacaa aacaaaccca acaatgattt tcactttgaa gtgttcaatt ttgtaccctg 5220
cagcatatgc agcaacaatc caacctgctg ggccatctgc aagagaatac caaacaaaaa 5280
acctggaaag aaaaccacca ccaagcccac aaaaaaacca accctcaaga caaccaaaaa 5340
agatcccaaa tcccaaacca caaaaccaaa ggaagtactc actaccaagc ctacaggaaa 5400
gccaaccatc aacaccacta aaacaaacat cagaactaca ctgctcacct ccaacaccaa 5460
aggaaatcca gaacacacaa gtcaagagga aaccctccac tcaaccacct ccgaaggcta 5520
tccaagccca tcacaagtcc acacaacatc cggtcaagag gaaaccctcc actcaaccac 5580
ctccgaaggc tatccaagcc catcacaagt ctacacaaca tccgagtacc tatcacaatc 5640
tctatcttca tccaacacaa caaaatgata gtcattaaaa agcacgcgtg tattgttgca 5700
aaaagccatg accaaatcaa acagaatcaa aatcaactct ggggcaaata acaatggagt 5760
tgccaatcct caaaacaaat gctattacca caatccttgc tgcagtcaca ctctgtttcg 5820
cttccagtca aaacatcact gaagaatttt atcaatcaac atgcagtgca gtcagcaaag 5880
gctatcttag tgctctaaga actggttggt atactagtgt tataactata gaattaagta 5940
atatcaagga aaataagtgt aatggtacag acgctaaggt aaaattaata aaacaagaat 6000
tagataaata taaaaatgct gtaacagaat tgcagttgct catgcaaagc acaccagcag 6060
ccaacaatcg agccagaaga gaactaccaa gatttatgaa ttatacactc aacaatacca 6120
aaaacaccaa tgtaacatta agtaagaaaa ggaaaagaag atttcttgga tttttgttag 6180
gtgttggatc tgcaatcgcc agtggcattg ccgtatccaa ggtcctgcac ctagaagggg 6240
aagtgaacaa aatcaaaagt gctctactat ccacaaacaa ggctgtagtc agcttatcta 6300
atggagtcag tgtcttaacc agcaaggtgt tagacctcaa aaactatata gataaacagt 6360
tgttacctat tgttaacaag caaagctgca gcatatcaaa cattgaaact gtgatagagt 6420
tccaacaaaa gaacaacaga ctactagaga ttaccagaga atttagtgtt aatgcaggtg 6480
taactactcc tgtaagcact tatatgttaa ctaatagtga gttattatca ttaatcaatg 6540
atatgcctat aacaaatgat cagaaaaagt taatgtccag caatgttcaa atagttagac 6600
agcaaagtta ctctatcatg tcaataataa aagaggaagt cttggcatat gtagtacaat 6660
taccactata tggtgtaata gatactcctt gttggaaact acacacatcc cctttatgta 6720
caaccaacac aaaggaagga tccaacatct gcttaacaag aaccgacaga ggatggtact 6780
gtgacaatgc aggatcagta tcctttttcc cacaagctga aacatgtaaa gttcaatcga 6840
atcgggtgtt ttgtgacaca atgaacagtt taacattacc aagtgaggta aatctctgca 6900
acattgacat attcaacccc aaatatgatt gcaaaattat gacttcaaaa acagatgtaa 6960
gcagctccgt tatcacatct ctaggagcca ttgtgtcatg ctatggcaaa accaaatgta 7020
cagcatccaa taaaaatcgt gggatcataa agacattctc taacgggtgt gattatgtat 7080
caaataaggg ggtggatact gtgtctgtag gtaatacatt atattatgta aataagcaag 7140
aaggcaaaag tctctatgta aaaggtgaac caataataaa tttctatgat ccattagtgt 7200
tcccctctga tgaatttgat gcatcaatat ctcaagtcaa tgagaaaatt aatcagagtc 7260
tagcatttat ccgtaaatca gatgaattat tacataatgt aaatgctggt aaatccacca 7320
caaatatcat gataactacc ataattatag taattatagt aatattgtta gcattaattg 7380
cagttggact gcttctatac tgcaaggcca gaagcacacc agtcacatta agtaaggatc 7440
aactgagtgg tataaataat attgcattta gtaactgaat aaaaatagca cctaatcata 7500
ttcttacaat ggttcgctat ttgaccatag ataacccatc tatcattaga ttatcctaaa 7560
atttgaactt catcacaact ttcatctata aaccatctca cttacacttt ttaagtagat 7620
ttctatttta tagttatata aaacagggcc cattgaatac caaattaact tactatttgt 7680
aaaaatgaga attggggcaa atatgtcacg aaggaatcct tgcaaattcg aaattcgagg 7740
tcattgcttg aatggtaaaa ggtgtcattt tagtcataat tattttgaat ggccacccca 7800
tgcactgctt gtaagacaaa actttatgtt aaacagaata cttaagtcta tggataaaag 7860
catagatact ttgtcagaaa taagtggagc tgcagagttg gacagaacag aagagtatgc 7920
cctcggtgta gttggagtgc tagagagtta tataggatca ataaataata taactaaaca 7980
atcagcatgt gttgccatga gcaaactcct tactgaactc aacagcgatg acatcaaaaa 8040
actaagggac aatgaagagc caaactcacc caaagtaaga gtgtacaata ctgtcatatc 8100
atatattgaa agcaacagga agaacaataa acaaactatc catctgttaa aaagattgcc 8160
agcagacgta ttgaagaaaa ccatcaaaaa cacattggat atccacaaga gcataaccat 8220
caataaccca aaagaatcaa ctgttagtga tacgaacgac catgccaaaa ataatgatac 8280
tacctgacaa atatccttgt agtataaatt ccatactaat aacaagtaat tgtagagtca 8340
ctatgtataa tcaaaaaaac acactatata tcaatcaaaa caaccaaaat agccatatat 8400
acccaccgga tcaaccattc aatgaaatcc attggacctc tcaagacttg attgatgcaa 8460
ctcaaaattt tctacaacat ctaggtatta ctgatgatat atacacaata tatatattag 8520
tgtcataata ctcaatccta atacttacca catcatcaaa ttattaactc aaacaattca 8580
agctatggga caaaatggat cccattatta gtggaaattc tgctaatgtt tatctaactg 8640
atagttattt aaaaggtgtt atttctttct cagaatgtaa cgctttagga agttacatat 8700
tcaatggtcc ttatctcaaa aatgattata ccaacttaat tagtagacaa aatccattaa 8760
tagaacacat aaatctaaag aaactaaata taacacagtc cttaatatct aagtatcata 8820
aaggtgaaat aaaaatagaa gaacctactt actttcagtc attacttatg acatacaaga 8880
gtatgacctc ttcagaacag actactacta ctaatttact taaaaagata ataagaagag 8940
ctatagaaat cagtgatgtc aaagtctatg ctatattgaa taaactgggg ctcaaagaaa 9000
aagacaagat taaatccaat aatggacaag atgaagacaa ctcagtcatt actaccataa 9060
tcaaagatga tatactttta gctgtcaagg ataatcaatc tcatcttaaa gcagacaaaa 9120
atcaatccac aaaacaaaaa gatacaatca aaacaacact tttgaagaaa ttaatgtgtt 9180
cgatgcaaca tcctccatca tggttaatac attggtttaa tttatacaca aaattaaaca 9240
gcatattaac acaatatcga tctagtgagg taaaaaacca tggttttata ttgatagata 9300
atcatactct tagtggattc caatttattt tgaatcaata tggttgtata gtttatcata 9360
aggaactcaa aagaattact gtgacaactt ataatcaatt cttgacatgg aaagatatta 9420
gccttagtag attaaatgtt tgtttgatta catggattag taactgtttg aacacattaa 9480
acaaaagctt aggcttaaga tgtggattca ataatgttat cttgacacaa ttattccttt 9540
atggagattg tatactaaaa ctattccaca atgaggggtt ctacataata aaagaggtag 9600
agggatttat tatgtctcta attttaaata taacagaaga agatcaattc agaaaacggt 9660
tttataatag tatgctcaac aacatcacag atgccgccaa caaagctcaa aaaaatctgc 9720
tatcaagagt atgtcataca ttattagata agacaatatc agataatata ataaatggca 9780
gatggataat tctattgagt aagttcctaa aattaattaa gcttgcaggt gacaataacc 9840
tcaacaatct gagtgaatta tattttttgt tcagaatatt tggacaccca atggtagatg 9900
aaagacaagc catggatgct gttaaagtta attgcaacga gaccaaattt tatttgttaa 9960
gtagtttgag tatgttaaga ggagctttta tatatagaat tataaaaggg tttgtaaata 10020
attacaacag atggcctact ttaagaaatg ccattgtctt acccttaaga tggttaactt 10080
actataaact aaacacttat ccttccttgt tggaacttac agaaagagat ttgattgttc 10140
tatcaggact acgtttctat cgagagtttc ggttgcctaa aaaagtggat cttgaaatga 10200
tcataaatga taaggctata tcacctccta aaaatttaat atggactagt ttccctagaa 10260
attatatgcc gtcacacata caaaattata tagaacatga aaaattaaaa ttctctgata 10320
gtgataaatc aagaagagta ttagagtatt atttaagaga taacaaattc aatgaatgtg 10380
atttacacaa ctgtgtagtt aatcaaagtt atcttaacaa cccgaatcat gtggtatcat 10440
tgacaggcaa agaaagagaa ctcagtgtag gtagaatgtt tgcaatgcaa ccaggaatgt 10500
tcagacaagt tcaaatatta gcagagaaaa tgatagcaga aaacatatta caatttttcc 10560
ctgaaagtct tacaagatat ggtgatctag aactacagaa aatattagaa ttgaaagcag 10620
gaataagtaa caaatcaaat cgttacaatg ataattacaa caattacatt agtaagtgct 10680
ctatcatcac agatctcagc aaattcaatc aagcatttcg atatgaaaca tcatgtattt 10740
gtagtgatgt actggatgaa ctgcatggtg tacaatctct attttcctgg ttacatttaa 10800
ctattcctca tgtcacaata atatgcacat ataggcatgc acccccctat ataaaggatc 10860
atattgtaga tcttaacaat gtagatgagc aaagtggact atatagatat catatgggtg 10920
gtatcgaagg gtggtgtcaa aaactatgga ccatagaagc tatatcacta ttagatctaa 10980
tatctctcaa agggaaattc tcaattactg ctttaattaa tggtgacaat caatcaatag 11040
atataagtaa accagtcaga ctcatggaag gtcaaactca tgctcaagca gattatttgc 11100
tagcattaaa tagtctcaaa ttactgtata aagagtatgc aggaataggc cacaaattaa 11160
aaggaactga gacttatata tcgagagata tgcaatttat gagtaaaacg atccaacata 11220
acggtgtata ttacccagct agtataaaga aagtcctaag agtgggaccg tggataaaca 11280
ctatacttga tgacttcaaa gtgagtctag aatctatagg tagtttgaca caagaattag 11340
aatatagagg tgaaagtcta ttatgcagtt taatatttag aaatgtatgg ttatataatc 11400
aaattgcatt acaacttaaa aatcatgcat tatgtaacaa caaattatat ttggatatat 11460
taaaagttct aaaacactta aaaacctttt ttaatcttga taacattgat acagcattaa 11520
cattgtatat gaatttgccc atgttatttg gtggtggtga tcccaacttg ttatatcgaa 11580
gtttctatag aagaactcct gatttcctca cagaggctat agttcactct gtgttcatac 11640
ttagttatta tacaaaccat gatttaaaag ataaacttca agatctgtca gatgatagat 11700
tgaataagtt cttaacatgc ataatcacgt ttgataaaaa ccccaatgct gaattcgtta 11760
cattgatgag agatcctcaa gctttaggat ctgagaggca agctaaaatt actagcgaaa 11820
tcaatagact ggcagttacc gaggttttga gcacagctcc aaacaaaata ttttccaaaa 11880
gtgcacaaca ctataccact acagagatag atcttaatga tattatgcaa aatatagaac 11940
ctacatatcc tcacgggcta agagttgttt atgagagttt acccttttat aaagcagaga 12000
aaatagtaaa tcttatatcc ggtacaaaat ctataactaa catactggaa aagacttctg 12060
ccatagactt aacagatatt gatagagcca ctgagatgat gaggaaaaac ataactttgc 12120
ttataaggat attaccatta gattgtaaca gagataaaag agaaatattg agtatggaaa 12180
acctaagtat tactgaatta agcaaatacg ttagagaaag atcttggtct ttatccaata 12240
tagttggtgt tacatcaccc agtatcatgt atacaatgga cataaaatat acaacaagca 12300
ctatagctag tggcataatc atagagaaat ataatgtcaa cagtttaaca cgtggtgaga 12360
gaggacccac taaaccatgg gttggttcat ctacacaaga gaaaaagaca atgccagttt 12420
ataatagaca agttttaacc aaaaaacaga gagatcaaat agatctatta gcaaaattgg 12480
attgggtgta tgcatctata gataacaagg atgaatttat ggaggaactt agcataggaa 12540
ctcttgggtt aacatatgag aaggccaaaa aattattccc acaatatttg agtgttaact 12600
atttgcatcg tcttacagtc agtagtagac catgtgaatt ccctgcatct ataccagctt 12660
atagaactac aaattatcac tttgatacta gccctattaa tcgcatatta acagaaaagt 12720
atggtgatga agatattgat atagtattcc aaaactgtat aagctttggc cttagcttaa 12780
tgtctgtagt agaacaattt actaatgtat gtcctaacag aattattctc atacccaagc 12840
ttaatgagat acatttgatg aaacctccca tattcacagg cgatgttgat attcacaagt 12900
taaaacaagt gatacaaaaa caacatatgt ttttaccaga caaaataagt ttgactcaat 12960
atgtggaatt attcttaagt aataaaacac tcaaatctgg atctaatgtt aattctaatt 13020
taatattggc gcataagata tctgactatt ttcataatac ttacattttg agtactaatt 13080
tagctggaca ttggattctt attatacaac ttatgaaaga ttctaagggt atttttgaaa 13140
aagattgggg agagggatat ataactgatc atatgttcat taatttgaaa gttttcttca 13200
atgcttataa gacatatctc ttgtgttttc ataaaggtta cggcagagca aagctggagt 13260
gtgatatgaa tacttcagat ctcctatgtg tattggaatt aatagacagt agttattgga 13320
agtctatgtc taaggtgttt ttagaacaaa aagttatcaa atacattctt agccaggatg 13380
caagtttaca tagagtaaaa ggatgtcata gcttcaaact atggtttctt aaacgtctta 13440
atgtagcaga attcacagtt tgcccttggg ttgttaacat agattatcat ccaacacata 13500
tgaaagcaat attaacttat attgatcttg ttagaatggg attgataaat atagatagaa 13560
tatacattaa aaataaacac aagttcaatg atgagtttta tacttctaat ctgttttaca 13620
ttaattataa cttctcagat aatactcatc tattaactaa acatataagg attgctaatt 13680
ccgaattaga aagtaattac aacaaattat atcatcctac accagaaacc ctagaaaata 13740
tactaaccaa tccggttaaa agtaatgaga aaaagacact gagtgactat tgtataggta 13800
aaaatgttga ctcaataatg ttaccatcgt tatctaataa gaagcttatt aaatcgtcta 13860
caatgattag aaccaattac agcagacaag atttgtataa tttatttcct acggttgtga 13920
ttgataaaat tatagatcat tcaggtaata cagccaaatc taaccaactt tacactacta 13980
cttctcatca aatatcctta gtgcacaata gcacatcact ttattgcatg cttccttggc 14040
atcatattaa tagattcaat tttgtattta gttctacagg ttgtaaaatt agtatagagt 14100
atattttaaa agatcttaaa attaaggatc ctaattgtat agcattcata ggtgaaggag 14160
cagggaattt attattgcgt acagtagtgg aacttcatcc tgatataaga tatatttaca 14220
gaagtctgaa agattgcaat gatcatagtt taccaattga gtttttaagg ctgtacaatg 14280
gacatatcaa cattgattat ggtgaaaatt tgaccattcc tgctacagat gcaaccaaca 14340
acattcattg gtcttattta catataaagt ttgctgaacc tatcagtctt tttgtctgtg 14400
atgctgaatt gcctgtaaca gtcaactgga gtaagattat aatagagtgg agcaagcatg 14460
taagaaaatg caagtactgt tcttcagtta ataaatgtac attgatagta aaatatcatg 14520
ctcaagatga tatcgatttc aaattagaca acataactat attaaaaact tatgtatgct 14580
taggtagtaa gttaaaggga tctgaagttt acttagtcct tacaataggt cctgcaaatg 14640
tgttcccagt atttaatgta gtacaaaatg ctaaattgat actatcaaga actaaaaatt 14700
tcatcatgcc taaaaaagct gataaagagt ctattgatgc aaatattaag agtttgatac 14760
cctttctttg ttaccctata acaaaaaaag gaattaatac tgcattgtct aaattaaaga 14820
gtgttgttag tggagatata ctatcatatt ctatagctgg acgtaatgaa gttttcagca 14880
ataaacttat aaatcataag catatgaaca tcttaaagtg gttcaatcat gttttaaatt 14940
tcagatcaac agaattaaac tataatcatt tatatatggt agaatctact tatcctcatc 15000
taagtgaatt gttaaacagc ttgacaacca atgaacttaa aaaactgatt aaaatcacag 15060
gtagtttgtt atacaacttt tataatgaat aatgagcaaa aatcttataa caaaaatagc 15120
tacacactaa cattgtattc aattatagtt attgaaaatt aataattata taatttttaa 15180
taacttctag tgaactaatc ctaaaattat cattttgatc taggaagaat aagtttaaat 15240
ccaaatctaa ttggtttata tgtatattaa ctaaattacg agatattagt ttttgacact 15300
ttttttctcg t 15311
<210> 3
<211> 15494
<212> DNA
<213> Artificial Sequence
<220>
<223> RSV backbone sequence_A
<400> 3
taatacgact cactataggt tttttcgcgt ctgatgaggc cgttaggccg aaactcctct 60
ccggagtcac gcgaaaaaat gcgtacaaca aacttgcgta aaccaaaaaa atggggcaaa 120
taagaatttg ataagtacca cttaaattta actcctttgg ttagaggcgc gccatgggca 180
gcaactcatt gagtatgata aaagttagat tgcaaaatct gtttgacaat gatgaagtag 240
cattgttaaa aataacatgc tatactgaca aattaataca gttaactaat gctttggcta 300
aggcagttat acatacaatc aaattgaatg gcattgtatt tgtgcatgtt attacaagta 360
gtgatatttg ccctaataat aatattgtag tgaaatccaa tttcacaaca atgccagtat 420
tacaaaatgg aggttatata tgggaaatga tggaattaac acactgctct caacctaatg 480
gcctaataga tgacaattgt gaaattaaat tctccaaaaa actaagtgat tcaacaatga 540
ccaattatat gaatcaatta tctgaattac ttggatttga cctcaatcca taaatcataa 600
taaatatcaa ctagcaaatc aatgtcacta acaccattag ttaatataaa acttgacaga 660
agataaaaat ggggcaaata aatcaattca gccgacccaa ccatggacac aacacacaat 720
gataccacac cacaaagact gatgatcaca gacatgaggc cattatcgct tgagactata 780
ataacatctc taaccagaga tatcataaca cataaattta tatacttgat aaatcatgaa 840
tgcatagtaa gaaaacttga tgaaagacag gccacattta catttctggt caactatgaa 900
atgaaactat tgcacaaagt gggaagcact aaatataaaa aatatactga atacaacaca 960
aaatatggca ctttccctat gccaatattt atcaatcatg atgggttctt agaatgcatt 1020
ggcattaagc ctaccaagca cacacccata atatacaagt atgatctcaa tccatgaata 1080
tcaaaccaag attcaaacaa tccgaaataa caactttatg cataatcaca ctccatagtc 1140
caaatggagc ctgaaaatta tagttattta aaattcctgc aggaaggaga gacataagat 1200
gaaagatggg gcaaatacaa aaatggctct tagcaaagtc aagttgaatg atacactcaa 1260
caaagatcaa cttctatcat ccagcaaata taccatccaa cggagcacag gagacagcat 1320
tgacactcct aattatgatg tgcagaaaca cattaataag ttatgtggca tgttattaat 1380
cacagaagat gctaatcata aattcactgg gttaataggt atgttatatg ctatgtctag 1440
attaggaaga gaagacacca taaaaatact caaagatgcg ggatatcatg ttaaggcaaa 1500
tggagtggat gtaacaacac atcgtcaaga cattaatggg aaagaaatga aatttgaagt 1560
gttaacatta gcaagcttaa caactgaaat tcaaatcaac attgagatag aatctagaaa 1620
atcctacaaa aaaatgctaa aagaaatggg agaggtggct ccagaataca ggcatgactc 1680
tcctgattgt gggatgataa tattatgtat agcggcatta gtaataacca aattagcagc 1740
aggagataga tcaggtctta cagctgtgat taggagagct aataatgtcc taaaaaatga 1800
aatgaaacgt tataaaggtt tattacccaa ggatatagcc aacagcttct atgaagtgtt 1860
tgaaaaatat cctcacttta tagatgtttt tgttcatttt ggtatagcac aatcttctac 1920
cagaggtggc agtagagttg aagggatttt tgcaggattg tttatgaatg cctatggtgc 1980
agggcaagtg atgttacggt ggggggtctt agcaaaatca gttaaaaaca ttatgttagg 2040
acacgctagt gtacaagcag aaatggaaca agttgtggag gtgtatgagt atgctcagaa 2100
attgggtgga gaagcaggat tctaccatat attgaacaac ccaaaagcat cactattatc 2160
tttgactcaa tttcctcact tctctagtgt agtattgggc aatgctgctg gcctaggcat 2220
aatgggagaa tacagaggta caccaaggaa tcaagattta tatgatgctg caaaagcata 2280
tgctgaacaa ctcaaagaaa atggtgtgat taactacagt gtattagatt tgacagcaga 2340
agaactagag gctatcaaac atcagcttaa tccaaaagat aatgatgtag agctttgagt 2400
taataaaaaa gtggggcaaa taaatcatca tggaaaagtt tgctcctgaa ttccatggag 2460
aagatgcaaa caacagagcc accaaattcc tagaatcaat aaagggcaaa ttcacatcac 2520
ccaaagatcc caagaaaaaa gatagtatca tatctgtcaa ctcaatagat atagaagtaa 2580
ccaaagaaag ccctataaca tcaaattcaa ccattataaa cccaataaat gagacagatg 2640
atactgtagg gaacaagccc aattatcaaa gaaagcctct agtaagtttc aaagaagacc 2700
ctacgccaag tgataatcct ttttcaaaac tatacaaaga aaccatagaa acatttgata 2760
acaatgaaga agaatctagc tattcatatg aagaaataaa tgatcagaca aacgataata 2820
taacagcaag attagatagg attgatgaga aattaagtga aatactagga atgcttcaca 2880
cattagtagt agcgagtgca ggacccacat ctgctcggga tggtataaga gatgccatgg 2940
ttggtttaag agaagaaatg atagaaaaaa tcagaactga agcattaatg accaatgaca 3000
gactagaagc tatggcaaga ctcaggaatg aagaaagtga aaagatggca aaagacacat 3060
cagatgaagt gtctctcaat ccaacatcag agaaactgaa caacctgttg gaagggaatg 3120
atagtgacaa tgatctatca cttgaagatt tctgattagc taccaaactg tacatcaaaa 3180
cacaacacca atagaaaacc aacaaacaaa ccaactcacc catccaacca aacatctatc 3240
tgctgattag ccaaccagcc aaaaaacaac cagccaatct aaaactagcc acccggaaaa 3300
aatcgatact atagttacaa aaaaagatgg ggcaaatatg gaaacatacg tgaataaact 3360
tcacgagggc tccacataca cagctgctgt tcaatacaat gtcctagaaa aagacgatga 3420
tcctgcatca cttacaatat gggtgcccat gttccaatca tccatgccag cagatctact 3480
cataaaagaa ctagccaatg tcaatatact agtgaaacaa atatccacac ccaagggacc 3540
ctcattaaga gtcatgataa actcaagaag tgcagtgcta gcacaaatgc ccagcaaatt 3600
taccatatgt gccaatgtgt ccttggatga aagaagcaag ctggcatatg atgtaaccac 3660
accctgtgaa attaaggcat gcagtctaac atgcctaaaa tcaaaaaata tgttaactac 3720
agttaaagat ctcactatga aaacactcaa cccaacacat gacatcattg ctttatgtga 3780
atttgaaaat atagtaacat caaaaaaagt cataatacca acatacctaa gatctatcag 3840
cgtcagaaat aaagatctga acacacttga aaatataaca accactgaat tcaaaaatgc 3900
cattacaaat gcaaaaatca tcccttactc aggattattg ttagtcatca cagtgactga 3960
caacaaagga gcattcaaat acataaagcc acaaagtcaa ttcatagtag atcttggagc 4020
ttacctagaa aaagaaagta tatattatgt tacaacaaat tggaagcaca cagctacacg 4080
atttgcaatc aaacccatgg aagattaacc tttttcctct acatcaatga gtagattcat 4140
acaaactttc taactacatt cttcacttca caatcataat caccaaccct ctgtggttca 4200
atcaatcaaa caaaactcat caagagttcc agatcatccc aagtcattgt tcatcagatc 4260
cagtactcaa ataagttaat aaaaaatcca catggggcaa ataatcattg agggaaatcc 4320
aactaatcac aacatctgtc aacatagaca agtcaacacg ctagataaaa tcaaccaatg 4380
gaaaatacat ccataactat agaattctca agcaaattct ggccttactt tacactaata 4440
cacatgataa caacaataat ctctttgata atcataatct ccatcatgat tgcaatacta 4500
aacaaactct gcgaatataa tgtattccat aacaaaacct ttgagctacc aagagctcga 4560
gtcaatacat agcattcacc aatctgatag ctcaaaacag taaccttgca tttgtaaatg 4620
aactaccctc acttcttcac aaaaccacat caacatctca ccatgcaagc catcatctat 4680
accataaagt agttaattaa aaatggccgg ccagtcataa caatgaacta ggatattaag 4740
accaaaaaca acgctggggc aaatgcaaac atgtccaaaa ccgaggacca acgcaccgcc 4800
aagacactag aaaggacctg ggacactttt aatcatctat tattcatatc atcgtgctta 4860
tacaagttaa atcttaaatc tatagcacaa atcacattat ctattttggc aattataatc 4920
tcaacctcac ttataattgc agccatcata ttcatagcct cggcaaacca caaagtcaca 4980
ctaacaactg caatcataca agatgcaacg aaccagatca agaacacaac cccaacatac 5040
ctcacccaga atccccagca tggaatcagc ttctccaatc tgtccggaac tacatcacaa 5100
tccaccacca tactagcttc aacaacacca agtgctgatt caaccccaca atccacaaca 5160
gtcaagatca aaaacacaac aacaacccaa atattaccta gcaaacccac cacaaaacaa 5220
cgccaaaata aaccacaaaa caaacccaac aatgattttc actttgaagt gttcaatttt 5280
gtaccctgca gcatatgcag caacaatcca acctgctggg ccatctgcaa gagaatacca 5340
aacaaaaaac ctggaaagaa aaccaccacc aagcccacaa aaaaaccaac cctcaagaca 5400
accaaaaaag atcccaaatc ccaaaccaca aaaccaaagg aagtactcac taccaagcct 5460
acaggaaagc caaccatcaa caccactaaa acaaacatca gaactacact gctcacctcc 5520
aacaccaaag gaaatccaga acacacaagt caagaggaaa ccctccactc aaccacctcc 5580
gaaggctatc caagcccatc acaagtccac acaacatccg gtcaagagga aaccctccac 5640
tcaaccacct ccgaaggcta tccaagccca tcacaagtct acacaacatc cgagtaccta 5700
tcacaatctc tatcttcatc caacacaaca aaatgatagt cattaaaaag cacgcgtgta 5760
ttgttgcaaa aagccatgac caaatcaaac agaatcaaaa tcaactctgg ggcaaataac 5820
aatggagttg ccaatcctca aaacaaatgc tattaccaca atccttgctg cagtcacact 5880
ctgtttcgct tccagtcaaa acatcactga agaattttat caatcaacat gcagtgcagt 5940
cagcaaaggc tatcttagtg ctctaagaac tggttggtat actagtgtta taactataga 6000
attaagtaat atcaaggaaa ataagtgtaa tggtacagac gctaaggtaa aattaataaa 6060
acaagaatta gataaatata aaaatgctgt aacagaattg cagttgctca tgcaaagcac 6120
accagcagcc aacaatcgag ccagaagaga actaccaaga tttatgaatt atacactcaa 6180
caataccaaa aacaccaatg taacattaag taagaaaagg aaaagaagat ttcttggatt 6240
tttgttaggt gttggatctg caatcgccag tggcattgcc gtatccaagg tcctgcacct 6300
agaaggggaa gtgaacaaaa tcaaaagtgc tctactatcc acaaacaagg ctgtagtcag 6360
cttatctaat ggagtcagtg tcttaaccag caaggtgtta gacctcaaaa actatataga 6420
taaacagttg ttacctattg ttaacaagca aagctgcagc atatcaaaca ttgaaactgt 6480
gatagagttc caacaaaaga acaacagact actagagatt accagagaat ttagtgttaa 6540
tgcaggtgta actactcctg taagcactta tatgttaact aatagtgagt tattatcatt 6600
aatcaatgat atgcctataa caaatgatca gaaaaagtta atgtccagca atgttcaaat 6660
agttagacag caaagttact ctatcatgtc aataataaaa gaggaagtct tggcatatgt 6720
agtacaatta ccactatatg gtgtaataga tactccttgt tggaaactac acacatcccc 6780
tttatgtaca accaacacaa aggaaggatc caacatctgc ttaacaagaa ccgacagagg 6840
atggtactgt gacaatgcag gatcagtatc ctttttccca caagctgaaa catgtaaagt 6900
tcaatcgaat cgggtgtttt gtgacacaat gaacagttta acattaccaa gtgaggtaaa 6960
tctctgcaac attgacatat tcaaccccaa atatgattgc aaaattatga cttcaaaaac 7020
agatgtaagc agctccgtta tcacatctct aggagccatt gtgtcatgct atggcaaaac 7080
caaatgtaca gcatccaata aaaatcgtgg gatcataaag acattctcta acgggtgtga 7140
ttatgtatca aataaggggg tggatactgt gtctgtaggt aatacattat attatgtaaa 7200
taagcaagaa ggcaaaagtc tctatgtaaa aggtgaacca ataataaatt tctatgatcc 7260
attagtgttc ccctctgatg aatttgatgc atcaatatct caagtcaatg agaaaattaa 7320
tcagagtcta gcatttatcc gtaaatcaga tgaattatta cataatgtaa atgctggtaa 7380
atccaccaca aatatcatga taactaccat aattatagta attatagtaa tattgttagc 7440
attaattgca gttggactgc ttctatactg caaggccaga agcacaccag tcacattaag 7500
taaggatcaa ctgagtggta taaataatat tgcatttagt aactgaataa aaatagcacc 7560
taatcatatt cttacaatgg ttcgctattt gaccatagat aacccatcta tcattagatt 7620
atcctaaaat ttgaacttca tcacaacttt catctataaa ccatctcact tacacttttt 7680
aagtagattt ctattttata gttatataaa acagggccca ttgaatacca aattaactta 7740
ctatttgtaa aaatgagaat tggggcaaat atgtcacgaa ggaatccttg caaattcgaa 7800
attcgaggtc attgcttgaa tggtaaaagg tgtcatttta gtcataatta ttttgaatgg 7860
ccaccccatg cactgcttgt aagacaaaac tttatgttaa acagaatact taagtctatg 7920
gataaaagca tagatacttt gtcagaaata agtggagctg cagagttgga cagaacagaa 7980
gagtatgccc tcggtgtagt tggagtgcta gagagttata taggatcaat aaataatata 8040
actaaacaat cagcatgtgt tgccatgagc aaactcctta ctgaactcaa cagcgatgac 8100
atcaaaaaac taagggacaa tgaagagcca aactcaccca aagtaagagt gtacaatact 8160
gtcatatcat atattgaaag caacaggaag aacaataaac aaactatcca tctgttaaaa 8220
agattgccag cagacgtatt gaagaaaacc atcaaaaaca cattggatat ccacaagagc 8280
ataaccatca ataacccaaa agaatcaact gttagtgata cgaacgacca tgccaaaaat 8340
aatgatacta cctgacaaat atccttgtag tataaattcc atactaataa caagtaattg 8400
tagagtcact atgtataatc aaaaaaacac actatatatc aatcaaaaca accaaaatag 8460
ccatatatac ccaccggatc aaccattcaa tgaaatccat tggacctctc aagacttgat 8520
tgatgcaact caaaattttc tacaacatct aggtattact gatgatatat acacaatata 8580
tatattagtg tcataatact caatcctaat acttaccaca tcatcaaatt attaactcaa 8640
acaattcaag ctatgggaca aaatggatcc cattattagt ggaaattctg ctaatgttta 8700
tctaactgat agttatttaa aaggtgttat ttctttctca gaatgtaacg ctttaggaag 8760
ttacatattc aatggtcctt atctcaaaaa tgattatacc aacttaatta gtagacaaaa 8820
tccattaata gaacacataa atctaaagaa actaaatata acacagtcct taatatctaa 8880
gtatcataaa ggtgaaataa aaatagaaga acctacttac tttcagtcat tacttatgac 8940
atacaagagt atgacctctt cagaacagac tactactact aatttactta aaaagataat 9000
aagaagagct atagaaatca gtgatgtcaa agtctatgct atattgaata aactggggct 9060
caaagaaaaa gacaagatta aatccaataa tggacaagat gaagacaact cagtcattac 9120
taccataatc aaagatgata tacttttagc tgtcaaggat aatcaatctc atcttaaagc 9180
agacaaaaat caatccacaa aacaaaaaga tacaatcaaa acaacacttt tgaagaaatt 9240
aatgtgttcg atgcaacatc ctccatcatg gttaatacat tggtttaatt tatacacaaa 9300
attaaacagc atattaacac aatatcgatc tagtgaggta aaaaaccatg gttttatatt 9360
gatagataat catactctta gtggattcca atttattttg aatcaatatg gttgtatagt 9420
ttatcataag gaactcaaaa gaattactgt gacaacttat aatcaattct tgacatggaa 9480
agatattagc cttagtagat taaatgtttg tttgattaca tggattagta actgtttgaa 9540
cacattaaac aaaagcttag gcttaagatg tggattcaat aatgttatct tgacacaatt 9600
attcctttat ggagattgta tactaaaact attccacaat gaggggttct acataataaa 9660
agaggtagag ggatttatta tgtctctaat tttaaatata acagaagaag atcaattcag 9720
aaaacggttt tataatagta tgctcaacaa catcacagat gccgccaaca aagctcaaaa 9780
aaatctgcta tcaagagtat gtcatacatt attagataag acaatatcag ataatataat 9840
aaatggcaga tggataattc tattgagtaa gttcctaaaa ttaattaagc ttgcaggtga 9900
caataacctc aacaatctga gtgaattata ttttttgttc agaatatttg gacacccaat 9960
ggtagatgaa agacaagcca tggatgctgt taaagttaat tgcaacgaga ccaaatttta 10020
tttgttaagt agtttgagta tgttaagagg agcttttata tatagaatta taaaagggtt 10080
tgtaaataat tacaacagat ggcctacttt aagaaatgcc attgtcttac ccttaagatg 10140
gttaacttac tataaactaa acacttatcc ttccttgttg gaacttacag aaagagattt 10200
gattgttcta tcaggactac gtttctatcg agagtttcgg ttgcctaaaa aagtggatct 10260
tgaaatgatc ataaatgata aggctatatc acctcctaaa aatttaatat ggactagttt 10320
ccctagaaat tatatgccgt cacacataca aaattatata gaacatgaaa aattaaaatt 10380
ctctgatagt gataaatcaa gaagagtatt agagtattat ttaagagata acaaattcaa 10440
tgaatgtgat ttacacaact gtgtagttaa tcaaagttat cttaacaacc cgaatcatgt 10500
ggtatcattg acaggcaaag aaagagaact cagtgtaggt agaatgtttg caatgcaacc 10560
aggaatgttc agacaagttc aaatattagc agagaaaatg atagcagaaa acatattaca 10620
atttttccct gaaagtctta caagatatgg tgatctagaa ctacagaaaa tattagaatt 10680
gaaagcagga ataagtaaca aatcaaatcg ttacaatgat aattacaaca attacattag 10740
taagtgctct atcatcacag atctcagcaa attcaatcaa gcatttcgat atgaaacatc 10800
atgtatttgt agtgatgtac tggatgaact gcatggtgta caatctctat tttcctggtt 10860
acatttaact attcctcatg tcacaataat atgcacatat aggcatgcac ccccctatat 10920
aaaggatcat attgtagatc ttaacaatgt agatgagcaa agtggactat atagatatca 10980
tatgggtggt atcgaagggt ggtgtcaaaa actatggacc atagaagcta tatcactatt 11040
agatctaata tctctcaaag ggaaattctc aattactgct ttaattaatg gtgacaatca 11100
atcaatagat ataagtaaac cagtcagact catggaaggt caaactcatg ctcaagcaga 11160
ttatttgcta gcattaaata gtctcaaatt actgtataaa gagtatgcag gaataggcca 11220
caaattaaaa ggaactgaga cttatatatc gagagatatg caatttatga gtaaaacgat 11280
ccaacataac ggtgtatatt acccagctag tataaagaaa gtcctaagag tgggaccgtg 11340
gataaacact atacttgatg acttcaaagt gagtctagaa tctataggta gtttgacaca 11400
agaattagaa tatagaggtg aaagtctatt atgcagttta atatttagaa atgtatggtt 11460
atataatcaa attgcattac aacttaaaaa tcatgcatta tgtaacaaca aattatattt 11520
ggatatatta aaagttctaa aacacttaaa aacctttttt aatcttgata acattgatac 11580
agcattaaca ttgtatatga atttgcccat gttatttggt ggtggtgatc ccaacttgtt 11640
atatcgaagt ttctatagaa gaactcctga tttcctcaca gaggctatag ttcactctgt 11700
gttcatactt agttattata caaaccatga tttaaaagat aaacttcaag atctgtcaga 11760
tgatagattg aataagttct taacatgcat aatcacgttt gataaaaacc ccaatgctga 11820
attcgttaca ttgatgagag atcctcaagc tttaggatct gagaggcaag ctaaaattac 11880
tagcgaaatc aatagactgg cagttaccga ggttttgagc acagctccaa acaaaatatt 11940
ttccaaaagt gcacaacact ataccactac agagatagat cttaatgata ttatgcaaaa 12000
tatagaacct acatatcctc acgggctaag agttgtttat gagagtttac ccttttataa 12060
agcagagaaa atagtaaatc ttatatccgg tacaaaatct ataactaaca tactggaaaa 12120
gacttctgcc atagacttaa cagatattga tagagccact gagatgatga ggaaaaacat 12180
aactttgctt ataaggatat taccattaga ttgtaacaga gataaaagag aaatattgag 12240
tatggaaaac ctaagtatta ctgaattaag caaatacgtt agagaaagat cttggtcttt 12300
atccaatata gttggtgtta catcacccag tatcatgtat acaatggaca taaaatatac 12360
aacaagcact atagctagtg gcataatcat agagaaatat aatgtcaaca gtttaacacg 12420
tggtgagaga ggacccacta aaccatgggt tggttcatct acacaagaga aaaagacaat 12480
gccagtttat aatagacaag ttttaaccaa aaaacagaga gatcaaatag atctattagc 12540
aaaattggat tgggtgtatg catctataga taacaaggat gaatttatgg aggaacttag 12600
cataggaact cttgggttaa catatgagaa ggccaaaaaa ttattcccac aatatttgag 12660
tgttaactat ttgcatcgtc ttacagtcag tagtagacca tgtgaattcc ctgcatctat 12720
accagcttat agaactacaa attatcactt tgatactagc cctattaatc gcatattaac 12780
agaaaagtat ggtgatgaag atattgatat agtattccaa aactgtataa gctttggcct 12840
tagcttaatg tctgtagtag aacaatttac taatgtatgt cctaacagaa ttattctcat 12900
acccaagctt aatgagatac atttgatgaa acctcccata ttcacaggcg atgttgatat 12960
tcacaagtta aaacaagtga tacaaaaaca acatatgttt ttaccagaca aaataagttt 13020
gactcaatat gtggaattat tcttaagtaa taaaacactc aaatctggat ctaatgttaa 13080
ttctaattta atattggcgc ataagatatc tgactatttt cataatactt acattttgag 13140
tactaattta gctggacatt ggattcttat tatacaactt atgaaagatt ctaagggtat 13200
ttttgaaaaa gattggggag agggatatat aactgatcat atgttcatta atttgaaagt 13260
tttcttcaat gcttataaga catatctctt gtgttttcat aaaggttacg gcagagcaaa 13320
gctggagtgt gatatgaata cttcagatct cctatgtgta ttggaattaa tagacagtag 13380
ttattggaag tctatgtcta aggtgttttt agaacaaaaa gttatcaaat acattcttag 13440
ccaggatgca agtttacata gagtaaaagg atgtcatagc ttcaaactat ggtttcttaa 13500
acgtcttaat gtagcagaat tcacagtttg cccttgggtt gttaacatag attatcatcc 13560
aacacatatg aaagcaatat taacttatat tgatcttgtt agaatgggat tgataaatat 13620
agatagaata tacattaaaa ataaacacaa gttcaatgat gagttttata cttctaatct 13680
gttttacatt aattataact tctcagataa tactcatcta ttaactaaac atataaggat 13740
tgctaattcc gaattagaaa gtaattacaa caaattatat catcctacac cagaaaccct 13800
agaaaatata ctaaccaatc cggttaaaag taatgagaaa aagacactga gtgactattg 13860
tataggtaaa aatgttgact caataatgtt accatcgtta tctaataaga agcttattaa 13920
atcgtctaca atgattagaa ccaattacag cagacaagat ttgtataatt tatttcctac 13980
ggttgtgatt gataaaatta tagatcattc aggtaataca gccaaatcta accaacttta 14040
cactactact tctcatcaaa tatccttagt gcacaatagc acatcacttt attgcatgct 14100
tccttggcat catattaata gattcaattt tgtatttagt tctacaggtt gtaaaattag 14160
tatagagtat attttaaaag atcttaaaat taaggatcct aattgtatag cattcatagg 14220
tgaaggagca gggaatttat tattgcgtac agtagtggaa cttcatcctg atataagata 14280
tatttacaga agtctgaaag attgcaatga tcatagttta ccaattgagt ttttaaggct 14340
gtacaatgga catatcaaca ttgattatgg tgaaaatttg accattcctg ctacagatgc 14400
aaccaacaac attcattggt cttatttaca tataaagttt gctgaaccta tcagtctttt 14460
tgtctgtgat gctgaattgc ctgtaacagt caactggagt aagattataa tagagtggag 14520
caagcatgta agaaaatgca agtactgttc ttcagttaat aaatgtacat tgatagtaaa 14580
atatcatgct caagatgata tcgatttcaa attagacaac ataactatat taaaaactta 14640
tgtatgctta ggtagtaagt taaagggatc tgaagtttac ttagtcctta caataggtcc 14700
tgcaaatgtg ttcccagtat ttaatgtagt acaaaatgct aaattgatac tatcaagaac 14760
taaaaatttc atcatgccta aaaaagctga taaagagtct attgatgcaa atattaagag 14820
tttgataccc tttctttgtt accctataac aaaaaaagga attaatactg cattgtctaa 14880
attaaagagt gttgttagtg gagatatact atcatattct atagctggac gtaatgaagt 14940
tttcagcaat aaacttataa atcataagca tatgaacatc ttaaagtggt tcaatcatgt 15000
tttaaatttc agatcaacag aattaaacta taatcattta tatatggtag aatctactta 15060
tcctcatcta agtgaattgt taaacagctt gacaaccaat gaacttaaaa aactgattaa 15120
aatcacaggt agtttgttat acaactttta taatgaataa tgagcaaaaa tcttataaca 15180
aaaatagcta cacactaaca ttgtattcaa ttatagttat tgaaaattaa taattatata 15240
atttttaata acttctagtg aactaatcct aaaattatca ttttgatcta ggaagaataa 15300
gtttaaatcc aaatctaatt ggtttatatg tatattaact aaattacgag atattagttt 15360
ttgacacttt ttttctcgtg gccggcatgg tcccagcctc ctcgctggcg ccggctgggc 15420
aacatgcttc ggcatggcga atgggactag cataacccct tggggcctct aaacgggtct 15480
tgaggggttt tttg 15494
<210> 4
<211> 15398
<212> DNA
<213> Artificial Sequence
<220>
<223> cRSVA_MVF_S
<400> 4
taatacgact cactataggt tttttcgcgt ctgatgaggc cgttaggccg aaactcctct 60
ccggagtcac gcgaaaaaat gcgtacaaca aacttgcgta aaccaaaaaa atggggcaaa 120
taagaatttg ataagtacca cttaaattta actcctttgg ttagaggcgc gccatgggca 180
gcaactcatt gagtatgata aaagttagat tgcaaaatct gtttgacaat gatgaagtag 240
cattgttaaa aataacatgc tatactgaca aattaataca gttaactaat gctttggcta 300
aggcagttat acatacaatc aaattgaatg gcattgtatt tgtgcatgtt attacaagta 360
gtgatatttg ccctaataat aatattgtag tgaaatccaa tttcacaaca atgccagtat 420
tacaaaatgg aggttatata tgggaaatga tggaattaac acactgctct caacctaatg 480
gcctaataga tgacaattgt gaaattaaat tctccaaaaa actaagtgat tcaacaatga 540
ccaattatat gaatcaatta tctgaattac ttggatttga cctcaatcca taaatcataa 600
taaatatcaa ctagcaaatc aatgtcacta acaccattag ttaatataaa acttgacaga 660
agataaaaat ggggcaaata aatcaattca gccgacccaa ccatggacac aacacacaat 720
gataccacac cacaaagact gatgatcaca gacatgaggc cattatcgct tgagactata 780
ataacatctc taaccagaga tatcataaca cataaattta tatacttgat aaatcatgaa 840
tgcatagtaa gaaaacttga tgaaagacag gccacattta catttctggt caactatgaa 900
atgaaactat tgcacaaagt gggaagcact aaatataaaa aatatactga atacaacaca 960
aaatatggca ctttccctat gccaatattt atcaatcatg atgggttctt agaatgcatt 1020
ggcattaagc ctaccaagca cacacccata atatacaagt atgatctcaa tccatgaata 1080
tcaaaccaag attcaaacaa tccgaaataa caactttatg cataatcaca ctccatagtc 1140
caaatggagc ctgaaaatta tagttattta aaattcctgc aggaaggaga gacataagat 1200
gaaagatggg gcaaatacaa aaatggctct tagcaaagtc aagttgaatg atacactcaa 1260
caaagatcaa cttctatcat ccagcaaata taccatccaa cggagcacag gagacagcat 1320
tgacactcct aattatgatg tgcagaaaca cattaataag ttatgtggca tgttattaat 1380
cacagaagat gctaatcata aattcactgg gttaataggt atgttatatg ctatgtctag 1440
attaggaaga gaagacacca taaaaatact caaagatgcg ggatatcatg ttaaggcaaa 1500
tggagtggat gtaacaacac atcgtcaaga cattaatggg aaagaaatga aatttgaagt 1560
gttaacatta gcaagcttaa caactgaaat tcaaatcaac attgagatag aatctagaaa 1620
atcctacaaa aaaatgctaa aagaaatggg agaggtggct ccagaataca ggcatgactc 1680
tcctgattgt gggatgataa tattatgtat agcggcatta gtaataacca aattagcagc 1740
aggagataga tcaggtctta cagctgtgat taggagagct aataatgtcc taaaaaatga 1800
aatgaaacgt tataaaggtt tattacccaa ggatatagcc aacagcttct atgaagtgtt 1860
tgaaaaatat cctcacttta tagatgtttt tgttcatttt ggtatagcac aatcttctac 1920
cagaggtggc agtagagttg aagggatttt tgcaggattg tttatgaatg cctatggtgc 1980
agggcaagtg atgttacggt ggggggtctt agcaaaatca gttaaaaaca ttatgttagg 2040
acacgctagt gtacaagcag aaatggaaca agttgtggag gtgtatgagt atgctcagaa 2100
attgggtgga gaagcaggat tctaccatat attgaacaac ccaaaagcat cactattatc 2160
tttgactcaa tttcctcact tctctagtgt agtattgggc aatgctgctg gcctaggcat 2220
aatgggagaa tacagaggta caccaaggaa tcaagattta tatgatgctg caaaagcata 2280
tgctgaacaa ctcaaagaaa atggtgtgat taactacagt gtattagatt tgacagcaga 2340
agaactagag gctatcaaac atcagcttaa tccaaaagat aatgatgtag agctttgagt 2400
taataaaaaa gtggggcaaa taaatcatca tggaaaagtt tgctcctgaa ttccatggag 2460
aagatgcaaa caacagagcc accaaattcc tagaatcaat aaagggcaaa ttcacatcac 2520
ccaaagatcc caagaaaaaa gatagtatca tatctgtcaa ctcaatagat atagaagtaa 2580
ccaaagaaag ccctataaca tcaaattcaa ccattataaa cccaataaat gagacagatg 2640
atactgtagg gaacaagccc aattatcaaa gaaagcctct agtaagtttc aaagaagacc 2700
ctacgccaag tgataatcct ttttcaaaac tatacaaaga aaccatagaa acatttgata 2760
acaatgaaga agaatctagc tattcatatg aagaaataaa tgatcagaca aacgataata 2820
taacagcaag attagatagg attgatgaga aattaagtga aatactagga atgcttcaca 2880
cattagtagt agcgagtgca ggacccacat ctgctcggga tggtataaga gatgccatgg 2940
ttggtttaag agaagaaatg atagaaaaaa tcagaactga agcattaatg accaatgaca 3000
gactagaagc tatggcaaga ctcaggaatg aagaaagtga aaagatggca aaagacacat 3060
cagatgaagt gtctctcaat ccaacatcag agaaactgaa caacctgttg gaagggaatg 3120
atagtgacaa tgatctatca cttgaagatt tctgattagc taccaaactg tacatcaaaa 3180
cacaacacca atagaaaacc aacaaacaaa ccaactcacc catccaacca aacatctatc 3240
tgctgattag ccaaccagcc aaaaaacaac cagccaatct aaaactagcc acccggaaaa 3300
aatcgatact atagttacaa aaaaagatgg ggcaaatatg gaaacatacg tgaataaact 3360
tcacgagggc tccacataca cagctgctgt tcaatacaat gtcctagaaa aagacgatga 3420
tcctgcatca cttacaatat gggtgcccat gttccaatca tccatgccag cagatctact 3480
cataaaagaa ctagccaatg tcaatatact agtgaaacaa atatccacac ccaagggacc 3540
ctcattaaga gtcatgataa actcaagaag tgcagtgcta gcacaaatgc ccagcaaatt 3600
taccatatgt gccaatgtgt ccttggatga aagaagcaag ctggcatatg atgtaaccac 3660
accctgtgaa attaaggcat gcagtctaac atgcctaaaa tcaaaaaata tgttaactac 3720
agttaaagat ctcactatga aaacactcaa cccaacacat gacatcattg ctttatgtga 3780
atttgaaaat atagtaacat caaaaaaagt cataatacca acatacctaa gatctatcag 3840
cgtcagaaat aaagatctga acacacttga aaatataaca accactgaat tcaaaaatgc 3900
cattacaaat gcaaaaatca tcccttactc aggattattg ttagtcatca cagtgactga 3960
caacaaagga gcattcaaat acataaagcc acaaagtcaa ttcatagtag atcttggagc 4020
ttacctagaa aaagaaagta tatattatgt tacaacaaat tggaagcaca cagctacacg 4080
atttgcaatc aaacccatgg aagattaacc tttttcctct acatcaatga gtagattcat 4140
acaaactttc taactacatt cttcacttca caatcataat caccaaccct ctgtggttca 4200
atcaatcaaa caaaactcat caagagttcc agatcatccc aagtcattgt tcatcagatc 4260
cagtactcaa ataagttaat aaaaaatcca catggggcaa ataatcattg agggaaatcc 4320
aactaatcac aacatctgtc aacatagaca agtcaacacg ctagataaaa tcaaccaatg 4380
gaaaatacat ccataactat agaattctca agcaaattct ggccttactt tacactaata 4440
cacatgataa caacaataat ctctttgata atcataatct ccatcatgat tgcaatacta 4500
aacaaactct gcgaatataa tgtattccat aacaaaacct ttgagctacc aagagctcga 4560
gtcaatacat agcattcacc aatctgatag ctcaaaacag taaccttgca tttgtaaatg 4620
aactaccctc acttcttcac aaaaccacat caacatctca ccatgcaagc catcatctat 4680
accataaagt agttaattaa aaatggccgg ccagtcataa caatgaacta ggatattaag 4740
accaaaaaca acgctggggc aaatgcaaac atgtccaaaa ccgaggacca acgcaccgcc 4800
aagacactag aaaggacctg ggacactttt aatcatctat tattcatatc atcgtgctta 4860
tacaagttaa atcttaaatc tatagcacaa atcacattat ctattttggc aattataatc 4920
tcaacctcac ttataattgc agccatcata ttcatagcct cggcaaacca caaagtcaca 4980
ctaacaactg caatcataca agatgcaacg aaccagatca agaacacaac cccaacatac 5040
ctcacccaga atccccagca tggaatcagc ttctccaatc tgtccggaac tacatcacaa 5100
tccaccacca tactagcttc aacaacacca agtgctgatt caaccccaca atccacaaca 5160
gtcaagatca aaaacacaac aacaacccaa atattaccta gcaaacccac cacaaaacaa 5220
cgccaaaata aaccacaaaa caaacccaac aatgattttc actttgaagt gttcaatttt 5280
gtaccctgca gcatatgcag caacaatcca acctgctggg ccatctgcaa gagaatacca 5340
aacaaaaaac ctggaaagaa aaccaccacc aagcccacaa aaaaaccaac cctcaagaca 5400
accaaaaaag atcccaaatc ccaaaccaca aaaccaaagg aagtactcac taccaagcct 5460
acaggaaagc caaccatcaa caccactaaa acaaacatca gaactacact gctcacctcc 5520
aacaccaaag gaaatccaga acacacaagt caagaggaaa ccctccactc aaccacctcc 5580
gaaggctatc caagcccatc acaagtccac acaacatccg gtcaagagga aaccctccac 5640
tcaaccacct ccgaaggcta tccaagccca tcacaagtct acacaacatc cgagtaccta 5700
tcacaatctc tatcttcatc caacacaaca aaatgatagt cattaaaaag cacgcgtgta 5760
ttgttgcaaa aagccatgac caaatcaaac agaatcaaaa tcaactctgg ggcaaataac 5820
aatgtccatc atgggtctca aggtgaacgt ctctgccata ttcatggcag tactgttaac 5880
tctccaaaca cccaccggtc aaatccattg gggcaatctc tctaagatag gggtggtagg 5940
aataggaagt gcaagctaca aagttatgac tcgttccagc catcaatcat tagtcataaa 6000
attaatgccc aatataactc tcctcaataa ctgcacgagg gtagagattg cagaatacag 6060
gagactactg agaacagttt tggaaccaat tagagatgca cttaatgcaa tgacccagaa 6120
tataagaccg gttcagagtg tagcttcaag taggagacac aagagatttg cgggagtagt 6180
cctggcaggt gcggccctag gcgttgccac agctgctcag ataacagccg gcattgcact 6240
tcaccagtcc atgctgaact ctcaagccat cgacaatctg agagcgagcc tggaaactac 6300
taatcaggca attgagacaa tcagacaagc agggcaggag atgatattgg ctgttcaggg 6360
tgtccaagac tacatcaata atgagctgat accgtctatg aaccaactat cttgtgattt 6420
aatcggccag aagctcgggc tcaaattgct cagatactat acagaaatcc tgtcattatt 6480
tggccccagt ttacgggacc ccatatctgc ggagatatct atccaggctt tgagctatgc 6540
gcttggagga gacatcaata aggtgttaga aaagctcgga tacagtggag gtgatttact 6600
gggcatctta gagagcggag gaataaaggc ccggataact cacgtcgaca cagagtccta 6660
cttcattgtc ctcagtatag cctatccgac gctgtccgag attaaggggg tgattgtcca 6720
ccggctagag ggggtctcgt acaacatagg ctctcaagag tggtatacca ctgtgcccaa 6780
gtatgttgca acccaagggt accttatctc gaattttgat gagtcatcgt gtactttcat 6840
gccagagggg actgtgtgca gccaaaatgc cttgtacccg atgagtcctc tgctccaaga 6900
atgcctccgg gggtacacca agtcctgtgc tcgtacactc gtatccgggt cttttgggaa 6960
ccggttcatt ttatcacaag ggaacctaat agccaattgt gcatcaatcc tttgcaagtg 7020
ttacacaaca ggaacgatca ttaatcaaga ccctgacaag atcctaacat acattgctgc 7080
cgatcactgc ccggtagtcg aggtgaacgg cgtgaccatc caagtcggga gcaggaggta 7140
tccagacgct gtgtacttgc acagaattga cctcggtcct cccatatcat tggagaggtt 7200
ggacgtaggg acaaatctgg ggaatgcaat tgctaagttg gaggatgcca aggaattgtt 7260
ggagtcatcg gaccagatat tgaggagtat gaaaggttta tcgagcacta gcataattat 7320
agtaattata gtaatattgt tagcattaat tgcagttgga ctgcttctat actgcaaggc 7380
cagaagcaca ccagtcacat taagtaagga tcaactgagt ggtataaata atattgcatt 7440
tagtaactga ataaaaatag cacctaatca tattcttaca atggttcgct atttgaccat 7500
agataaccca tctatcatta gattatccta aaatttgaac ttcatcacaa ctttcatcta 7560
taaaccatct cacttacact ttttaagtag atttctattt tatagttata taaaacaggg 7620
cccattgaat accaaattaa cttactattt gtaaaaatga gaattggggc aaatatgtca 7680
cgaaggaatc cttgcaaatt cgaaattcga ggtcattgct tgaatggtaa aaggtgtcat 7740
tttagtcata attattttga atggccaccc catgcactgc ttgtaagaca aaactttatg 7800
ttaaacagaa tacttaagtc tatggataaa agcatagata ctttgtcaga aataagtgga 7860
gctgcagagt tggacagaac agaagagtat gccctcggtg tagttggagt gctagagagt 7920
tatataggat caataaataa tataactaaa caatcagcat gtgttgccat gagcaaactc 7980
cttactgaac tcaacagcga tgacatcaaa aaactaaggg acaatgaaga gccaaactca 8040
cccaaagtaa gagtgtacaa tactgtcata tcatatattg aaagcaacag gaagaacaat 8100
aaacaaacta tccatctgtt aaaaagattg ccagcagacg tattgaagaa aaccatcaaa 8160
aacacattgg atatccacaa gagcataacc atcaataacc caaaagaatc aactgttagt 8220
gatacgaacg accatgccaa aaataatgat actacctgac aaatatcctt gtagtataaa 8280
ttccatacta ataacaagta attgtagagt cactatgtat aatcaaaaaa acacactata 8340
tatcaatcaa aacaaccaaa atagccatat atacccaccg gatcaaccat tcaatgaaat 8400
ccattggacc tctcaagact tgattgatgc aactcaaaat tttctacaac atctaggtat 8460
tactgatgat atatacacaa tatatatatt agtgtcataa tactcaatcc taatacttac 8520
cacatcatca aattattaac tcaaacaatt caagctatgg gacaaaatgg atcccattat 8580
tagtggaaat tctgctaatg tttatctaac tgatagttat ttaaaaggtg ttatttcttt 8640
ctcagaatgt aacgctttag gaagttacat attcaatggt ccttatctca aaaatgatta 8700
taccaactta attagtagac aaaatccatt aatagaacac ataaatctaa agaaactaaa 8760
tataacacag tccttaatat ctaagtatca taaaggtgaa ataaaaatag aagaacctac 8820
ttactttcag tcattactta tgacatacaa gagtatgacc tcttcagaac agactactac 8880
tactaattta cttaaaaaga taataagaag agctatagaa atcagtgatg tcaaagtcta 8940
tgctatattg aataaactgg ggctcaaaga aaaagacaag attaaatcca ataatggaca 9000
agatgaagac aactcagtca ttactaccat aatcaaagat gatatacttt tagctgtcaa 9060
ggataatcaa tctcatctta aagcagacaa aaatcaatcc acaaaacaaa aagatacaat 9120
caaaacaaca cttttgaaga aattaatgtg ttcgatgcaa catcctccat catggttaat 9180
acattggttt aatttataca caaaattaaa cagcatatta acacaatatc gatctagtga 9240
ggtaaaaaac catggtttta tattgataga taatcatact cttagtggat tccaatttat 9300
tttgaatcaa tatggttgta tagtttatca taaggaactc aaaagaatta ctgtgacaac 9360
ttataatcaa ttcttgacat ggaaagatat tagccttagt agattaaatg tttgtttgat 9420
tacatggatt agtaactgtt tgaacacatt aaacaaaagc ttaggcttaa gatgtggatt 9480
caataatgtt atcttgacac aattattcct ttatggagat tgtatactaa aactattcca 9540
caatgagggg ttctacataa taaaagaggt agagggattt attatgtctc taattttaaa 9600
tataacagaa gaagatcaat tcagaaaacg gttttataat agtatgctca acaacatcac 9660
agatgccgcc aacaaagctc aaaaaaatct gctatcaaga gtatgtcata cattattaga 9720
taagacaata tcagataata taataaatgg cagatggata attctattga gtaagttcct 9780
aaaattaatt aagcttgcag gtgacaataa cctcaacaat ctgagtgaat tatatttttt 9840
gttcagaata tttggacacc caatggtaga tgaaagacaa gccatggatg ctgttaaagt 9900
taattgcaac gagaccaaat tttatttgtt aagtagtttg agtatgttaa gaggagcttt 9960
tatatataga attataaaag ggtttgtaaa taattacaac agatggccta ctttaagaaa 10020
tgccattgtc ttacccttaa gatggttaac ttactataaa ctaaacactt atccttcctt 10080
gttggaactt acagaaagag atttgattgt tctatcagga ctacgtttct atcgagagtt 10140
tcggttgcct aaaaaagtgg atcttgaaat gatcataaat gataaggcta tatcacctcc 10200
taaaaattta atatggacta gtttccctag aaattatatg ccgtcacaca tacaaaatta 10260
tatagaacat gaaaaattaa aattctctga tagtgataaa tcaagaagag tattagagta 10320
ttatttaaga gataacaaat tcaatgaatg tgatttacac aactgtgtag ttaatcaaag 10380
ttatcttaac aacccgaatc atgtggtatc attgacaggc aaagaaagag aactcagtgt 10440
aggtagaatg tttgcaatgc aaccaggaat gttcagacaa gttcaaatat tagcagagaa 10500
aatgatagca gaaaacatat tacaattttt ccctgaaagt cttacaagat atggtgatct 10560
agaactacag aaaatattag aattgaaagc aggaataagt aacaaatcaa atcgttacaa 10620
tgataattac aacaattaca ttagtaagtg ctctatcatc acagatctca gcaaattcaa 10680
tcaagcattt cgatatgaaa catcatgtat ttgtagtgat gtactggatg aactgcatgg 10740
tgtacaatct ctattttcct ggttacattt aactattcct catgtcacaa taatatgcac 10800
atataggcat gcacccccct atataaagga tcatattgta gatcttaaca atgtagatga 10860
gcaaagtgga ctatatagat atcatatggg tggtatcgaa gggtggtgtc aaaaactatg 10920
gaccatagaa gctatatcac tattagatct aatatctctc aaagggaaat tctcaattac 10980
tgctttaatt aatggtgaca atcaatcaat agatataagt aaaccagtca gactcatgga 11040
aggtcaaact catgctcaag cagattattt gctagcatta aatagtctca aattactgta 11100
taaagagtat gcaggaatag gccacaaatt aaaaggaact gagacttata tatcgagaga 11160
tatgcaattt atgagtaaaa cgatccaaca taacggtgta tattacccag ctagtataaa 11220
gaaagtccta agagtgggac cgtggataaa cactatactt gatgacttca aagtgagtct 11280
agaatctata ggtagtttga cacaagaatt agaatataga ggtgaaagtc tattatgcag 11340
tttaatattt agaaatgtat ggttatataa tcaaattgca ttacaactta aaaatcatgc 11400
attatgtaac aacaaattat atttggatat attaaaagtt ctaaaacact taaaaacctt 11460
ttttaatctt gataacattg atacagcatt aacattgtat atgaatttgc ccatgttatt 11520
tggtggtggt gatcccaact tgttatatcg aagtttctat agaagaactc ctgatttcct 11580
cacagaggct atagttcact ctgtgttcat acttagttat tatacaaacc atgatttaaa 11640
agataaactt caagatctgt cagatgatag attgaataag ttcttaacat gcataatcac 11700
gtttgataaa aaccccaatg ctgaattcgt tacattgatg agagatcctc aagctttagg 11760
atctgagagg caagctaaaa ttactagcga aatcaataga ctggcagtta ccgaggtttt 11820
gagcacagct ccaaacaaaa tattttccaa aagtgcacaa cactatacca ctacagagat 11880
agatcttaat gatattatgc aaaatataga acctacatat cctcacgggc taagagttgt 11940
ttatgagagt ttaccctttt ataaagcaga gaaaatagta aatcttatat ccggtacaaa 12000
atctataact aacatactgg aaaagacttc tgccatagac ttaacagata ttgatagagc 12060
cactgagatg atgaggaaaa acataacttt gcttataagg atattaccat tagattgtaa 12120
cagagataaa agagaaatat tgagtatgga aaacctaagt attactgaat taagcaaata 12180
cgttagagaa agatcttggt ctttatccaa tatagttggt gttacatcac ccagtatcat 12240
gtatacaatg gacataaaat atacaacaag cactatagct agtggcataa tcatagagaa 12300
atataatgtc aacagtttaa cacgtggtga gagaggaccc actaaaccat gggttggttc 12360
atctacacaa gagaaaaaga caatgccagt ttataataga caagttttaa ccaaaaaaca 12420
gagagatcaa atagatctat tagcaaaatt ggattgggtg tatgcatcta tagataacaa 12480
ggatgaattt atggaggaac ttagcatagg aactcttggg ttaacatatg agaaggccaa 12540
aaaattattc ccacaatatt tgagtgttaa ctatttgcat cgtcttacag tcagtagtag 12600
accatgtgaa ttccctgcat ctataccagc ttatagaact acaaattatc actttgatac 12660
tagccctatt aatcgcatat taacagaaaa gtatggtgat gaagatattg atatagtatt 12720
ccaaaactgt ataagctttg gccttagctt aatgtctgta gtagaacaat ttactaatgt 12780
atgtcctaac agaattattc tcatacccaa gcttaatgag atacatttga tgaaacctcc 12840
catattcaca ggcgatgttg atattcacaa gttaaaacaa gtgatacaaa aacaacatat 12900
gtttttacca gacaaaataa gtttgactca atatgtggaa ttattcttaa gtaataaaac 12960
actcaaatct ggatctaatg ttaattctaa tttaatattg gcgcataaga tatctgacta 13020
ttttcataat acttacattt tgagtactaa tttagctgga cattggattc ttattataca 13080
acttatgaaa gattctaagg gtatttttga aaaagattgg ggagagggat atataactga 13140
tcatatgttc attaatttga aagttttctt caatgcttat aagacatatc tcttgtgttt 13200
tcataaaggt tacggcagag caaagctgga gtgtgatatg aatacttcag atctcctatg 13260
tgtattggaa ttaatagaca gtagttattg gaagtctatg tctaaggtgt ttttagaaca 13320
aaaagttatc aaatacattc ttagccagga tgcaagttta catagagtaa aaggatgtca 13380
tagcttcaaa ctatggtttc ttaaacgtct taatgtagca gaattcacag tttgcccttg 13440
ggttgttaac atagattatc atccaacaca tatgaaagca atattaactt atattgatct 13500
tgttagaatg ggattgataa atatagatag aatatacatt aaaaataaac acaagttcaa 13560
tgatgagttt tatacttcta atctgtttta cattaattat aacttctcag ataatactca 13620
tctattaact aaacatataa ggattgctaa ttccgaatta gaaagtaatt acaacaaatt 13680
atatcatcct acaccagaaa ccctagaaaa tatactaacc aatccggtta aaagtaatga 13740
gaaaaagaca ctgagtgact attgtatagg taaaaatgtt gactcaataa tgttaccatc 13800
gttatctaat aagaagctta ttaaatcgtc tacaatgatt agaaccaatt acagcagaca 13860
agatttgtat aatttatttc ctacggttgt gattgataaa attatagatc attcaggtaa 13920
tacagccaaa tctaaccaac tttacactac tacttctcat caaatatcct tagtgcacaa 13980
tagcacatca ctttattgca tgcttccttg gcatcatatt aatagattca attttgtatt 14040
tagttctaca ggttgtaaaa ttagtataga gtatatttta aaagatctta aaattaagga 14100
tcctaattgt atagcattca taggtgaagg agcagggaat ttattattgc gtacagtagt 14160
ggaacttcat cctgatataa gatatattta cagaagtctg aaagattgca atgatcatag 14220
tttaccaatt gagtttttaa ggctgtacaa tggacatatc aacattgatt atggtgaaaa 14280
tttgaccatt cctgctacag atgcaaccaa caacattcat tggtcttatt tacatataaa 14340
gtttgctgaa cctatcagtc tttttgtctg tgatgctgaa ttgcctgtaa cagtcaactg 14400
gagtaagatt ataatagagt ggagcaagca tgtaagaaaa tgcaagtact gttcttcagt 14460
taataaatgt acattgatag taaaatatca tgctcaagat gatatcgatt tcaaattaga 14520
caacataact atattaaaaa cttatgtatg cttaggtagt aagttaaagg gatctgaagt 14580
ttacttagtc cttacaatag gtcctgcaaa tgtgttccca gtatttaatg tagtacaaaa 14640
tgctaaattg atactatcaa gaactaaaaa tttcatcatg cctaaaaaag ctgataaaga 14700
gtctattgat gcaaatatta agagtttgat accctttctt tgttacccta taacaaaaaa 14760
aggaattaat actgcattgt ctaaattaaa gagtgttgtt agtggagata tactatcata 14820
ttctatagct ggacgtaatg aagttttcag caataaactt ataaatcata agcatatgaa 14880
catcttaaag tggttcaatc atgttttaaa tttcagatca acagaattaa actataatca 14940
tttatatatg gtagaatcta cttatcctca tctaagtgaa ttgttaaaca gcttgacaac 15000
caatgaactt aaaaaactga ttaaaatcac aggtagtttg ttatacaact tttataatga 15060
ataatgagca aaaatcttat aacaaaaata gctacacact aacattgtat tcaattatag 15120
ttattgaaaa ttaataatta tataattttt aataacttct agtgaactaa tcctaaaatt 15180
atcattttga tctaggaaga ataagtttaa atccaaatct aattggttta tatgtatatt 15240
aactaaatta cgagatatta gtttttgaca ctttttttct cgtggccggc atggtcccag 15300
cctcctcgct ggcgccggct gggcaacatg cttcggcatg gcgaatggga ctagcataac 15360
cccttggggc ctctaaacgg gtcttgaggg gttttttg 15398
<210> 5
<211> 15407
<212> DNA
<213> Artificial Sequence
<220>
<223> cRSVA_NDVF_S
<400> 5
taatacgact cactataggt tttttcgcgt ctgatgaggc cgttaggccg aaactcctct 60
ccggagtcac gcgaaaaaat gcgtacaaca aacttgcgta aaccaaaaaa atggggcaaa 120
taagaatttg ataagtacca cttaaattta actcctttgg ttagaggcgc gccatgggca 180
gcaactcatt gagtatgata aaagttagat tgcaaaatct gtttgacaat gatgaagtag 240
cattgttaaa aataacatgc tatactgaca aattaataca gttaactaat gctttggcta 300
aggcagttat acatacaatc aaattgaatg gcattgtatt tgtgcatgtt attacaagta 360
gtgatatttg ccctaataat aatattgtag tgaaatccaa tttcacaaca atgccagtat 420
tacaaaatgg aggttatata tgggaaatga tggaattaac acactgctct caacctaatg 480
gcctaataga tgacaattgt gaaattaaat tctccaaaaa actaagtgat tcaacaatga 540
ccaattatat gaatcaatta tctgaattac ttggatttga cctcaatcca taaatcataa 600
taaatatcaa ctagcaaatc aatgtcacta acaccattag ttaatataaa acttgacaga 660
agataaaaat ggggcaaata aatcaattca gccgacccaa ccatggacac aacacacaat 720
gataccacac cacaaagact gatgatcaca gacatgaggc cattatcgct tgagactata 780
ataacatctc taaccagaga tatcataaca cataaattta tatacttgat aaatcatgaa 840
tgcatagtaa gaaaacttga tgaaagacag gccacattta catttctggt caactatgaa 900
atgaaactat tgcacaaagt gggaagcact aaatataaaa aatatactga atacaacaca 960
aaatatggca ctttccctat gccaatattt atcaatcatg atgggttctt agaatgcatt 1020
ggcattaagc ctaccaagca cacacccata atatacaagt atgatctcaa tccatgaata 1080
tcaaaccaag attcaaacaa tccgaaataa caactttatg cataatcaca ctccatagtc 1140
caaatggagc ctgaaaatta tagttattta aaattcctgc aggaaggaga gacataagat 1200
gaaagatggg gcaaatacaa aaatggctct tagcaaagtc aagttgaatg atacactcaa 1260
caaagatcaa cttctatcat ccagcaaata taccatccaa cggagcacag gagacagcat 1320
tgacactcct aattatgatg tgcagaaaca cattaataag ttatgtggca tgttattaat 1380
cacagaagat gctaatcata aattcactgg gttaataggt atgttatatg ctatgtctag 1440
attaggaaga gaagacacca taaaaatact caaagatgcg ggatatcatg ttaaggcaaa 1500
tggagtggat gtaacaacac atcgtcaaga cattaatggg aaagaaatga aatttgaagt 1560
gttaacatta gcaagcttaa caactgaaat tcaaatcaac attgagatag aatctagaaa 1620
atcctacaaa aaaatgctaa aagaaatggg agaggtggct ccagaataca ggcatgactc 1680
tcctgattgt gggatgataa tattatgtat agcggcatta gtaataacca aattagcagc 1740
aggagataga tcaggtctta cagctgtgat taggagagct aataatgtcc taaaaaatga 1800
aatgaaacgt tataaaggtt tattacccaa ggatatagcc aacagcttct atgaagtgtt 1860
tgaaaaatat cctcacttta tagatgtttt tgttcatttt ggtatagcac aatcttctac 1920
cagaggtggc agtagagttg aagggatttt tgcaggattg tttatgaatg cctatggtgc 1980
agggcaagtg atgttacggt ggggggtctt agcaaaatca gttaaaaaca ttatgttagg 2040
acacgctagt gtacaagcag aaatggaaca agttgtggag gtgtatgagt atgctcagaa 2100
attgggtgga gaagcaggat tctaccatat attgaacaac ccaaaagcat cactattatc 2160
tttgactcaa tttcctcact tctctagtgt agtattgggc aatgctgctg gcctaggcat 2220
aatgggagaa tacagaggta caccaaggaa tcaagattta tatgatgctg caaaagcata 2280
tgctgaacaa ctcaaagaaa atggtgtgat taactacagt gtattagatt tgacagcaga 2340
agaactagag gctatcaaac atcagcttaa tccaaaagat aatgatgtag agctttgagt 2400
taataaaaaa gtggggcaaa taaatcatca tggaaaagtt tgctcctgaa ttccatggag 2460
aagatgcaaa caacagagcc accaaattcc tagaatcaat aaagggcaaa ttcacatcac 2520
ccaaagatcc caagaaaaaa gatagtatca tatctgtcaa ctcaatagat atagaagtaa 2580
ccaaagaaag ccctataaca tcaaattcaa ccattataaa cccaataaat gagacagatg 2640
atactgtagg gaacaagccc aattatcaaa gaaagcctct agtaagtttc aaagaagacc 2700
ctacgccaag tgataatcct ttttcaaaac tatacaaaga aaccatagaa acatttgata 2760
acaatgaaga agaatctagc tattcatatg aagaaataaa tgatcagaca aacgataata 2820
taacagcaag attagatagg attgatgaga aattaagtga aatactagga atgcttcaca 2880
cattagtagt agcgagtgca ggacccacat ctgctcggga tggtataaga gatgccatgg 2940
ttggtttaag agaagaaatg atagaaaaaa tcagaactga agcattaatg accaatgaca 3000
gactagaagc tatggcaaga ctcaggaatg aagaaagtga aaagatggca aaagacacat 3060
cagatgaagt gtctctcaat ccaacatcag agaaactgaa caacctgttg gaagggaatg 3120
atagtgacaa tgatctatca cttgaagatt tctgattagc taccaaactg tacatcaaaa 3180
cacaacacca atagaaaacc aacaaacaaa ccaactcacc catccaacca aacatctatc 3240
tgctgattag ccaaccagcc aaaaaacaac cagccaatct aaaactagcc acccggaaaa 3300
aatcgatact atagttacaa aaaaagatgg ggcaaatatg gaaacatacg tgaataaact 3360
tcacgagggc tccacataca cagctgctgt tcaatacaat gtcctagaaa aagacgatga 3420
tcctgcatca cttacaatat gggtgcccat gttccaatca tccatgccag cagatctact 3480
cataaaagaa ctagccaatg tcaatatact agtgaaacaa atatccacac ccaagggacc 3540
ctcattaaga gtcatgataa actcaagaag tgcagtgcta gcacaaatgc ccagcaaatt 3600
taccatatgt gccaatgtgt ccttggatga aagaagcaag ctggcatatg atgtaaccac 3660
accctgtgaa attaaggcat gcagtctaac atgcctaaaa tcaaaaaata tgttaactac 3720
agttaaagat ctcactatga aaacactcaa cccaacacat gacatcattg ctttatgtga 3780
atttgaaaat atagtaacat caaaaaaagt cataatacca acatacctaa gatctatcag 3840
cgtcagaaat aaagatctga acacacttga aaatataaca accactgaat tcaaaaatgc 3900
cattacaaat gcaaaaatca tcccttactc aggattattg ttagtcatca cagtgactga 3960
caacaaagga gcattcaaat acataaagcc acaaagtcaa ttcatagtag atcttggagc 4020
ttacctagaa aaagaaagta tatattatgt tacaacaaat tggaagcaca cagctacacg 4080
atttgcaatc aaacccatgg aagattaacc tttttcctct acatcaatga gtagattcat 4140
acaaactttc taactacatt cttcacttca caatcataat caccaaccct ctgtggttca 4200
atcaatcaaa caaaactcat caagagttcc agatcatccc aagtcattgt tcatcagatc 4260
cagtactcaa ataagttaat aaaaaatcca catggggcaa ataatcattg agggaaatcc 4320
aactaatcac aacatctgtc aacatagaca agtcaacacg ctagataaaa tcaaccaatg 4380
gaaaatacat ccataactat agaattctca agcaaattct ggccttactt tacactaata 4440
cacatgataa caacaataat ctctttgata atcataatct ccatcatgat tgcaatacta 4500
aacaaactct gcgaatataa tgtattccat aacaaaacct ttgagctacc aagagctcga 4560
gtcaatacat agcattcacc aatctgatag ctcaaaacag taaccttgca tttgtaaatg 4620
aactaccctc acttcttcac aaaaccacat caacatctca ccatgcaagc catcatctat 4680
accataaagt agttaattaa aaatggccgg ccagtcataa caatgaacta ggatattaag 4740
accaaaaaca acgctggggc aaatgcaaac atgtccaaaa ccgaggacca acgcaccgcc 4800
aagacactag aaaggacctg ggacactttt aatcatctat tattcatatc atcgtgctta 4860
tacaagttaa atcttaaatc tatagcacaa atcacattat ctattttggc aattataatc 4920
tcaacctcac ttataattgc agccatcata ttcatagcct cggcaaacca caaagtcaca 4980
ctaacaactg caatcataca agatgcaacg aaccagatca agaacacaac cccaacatac 5040
ctcacccaga atccccagca tggaatcagc ttctccaatc tgtccggaac tacatcacaa 5100
tccaccacca tactagcttc aacaacacca agtgctgatt caaccccaca atccacaaca 5160
gtcaagatca aaaacacaac aacaacccaa atattaccta gcaaacccac cacaaaacaa 5220
cgccaaaata aaccacaaaa caaacccaac aatgattttc actttgaagt gttcaatttt 5280
gtaccctgca gcatatgcag caacaatcca acctgctggg ccatctgcaa gagaatacca 5340
aacaaaaaac ctggaaagaa aaccaccacc aagcccacaa aaaaaccaac cctcaagaca 5400
accaaaaaag atcccaaatc ccaaaccaca aaaccaaagg aagtactcac taccaagcct 5460
acaggaaagc caaccatcaa caccactaaa acaaacatca gaactacact gctcacctcc 5520
aacaccaaag gaaatccaga acacacaagt caagaggaaa ccctccactc aaccacctcc 5580
gaaggctatc caagcccatc acaagtccac acaacatccg gtcaagagga aaccctccac 5640
tcaaccacct ccgaaggcta tccaagccca tcacaagtct acacaacatc cgagtaccta 5700
tcacaatctc tatcttcatc caacacaaca aaatgatagt cattaaaaag cacgcgtgta 5760
ttgttgcaaa aagccatgac caaatcaaac agaatcaaaa tcaactctgg ggcaaataac 5820
aatgggttcc aagtcttcta ccaggttccc agtacctcta atgctgaccg tccgagtcat 5880
gctggcactg agttgcgtct gtccggccag cgcccttgat ggcaggcctc ttgcggctgc 5940
agggattgtg gtaacaggag acaaagcggt caacatatac acatcatctc agacagggtc 6000
aatcataatc aagttactcc cgaatatgcc caaggataaa gaggcgtgtg caaaagcacc 6060
gttggaggca tacaacagga cattgactac tttgctcacc cctcttggtg attctatccg 6120
taggatacaa gagtctgtga ccacgtccgg aggaagaaaa cagggacgcc ttataggagc 6180
cattatcggt ggtgtagctc tcggggtcgc gaccgctgca caaataacag cagcctcggc 6240
tttgatacaa gccaatcaaa atgctgccaa catcctccgg ctcaaagaga gcattgctgc 6300
aaccaatgag gctgtacacg aggtcactga cggattatca caactagcag tggcagttgg 6360
gaagatgcag caatttgtta atgaccagtt taataagaca gcccaggaat tggactgtat 6420
aaaaattgca cagcaagttg gtgtagaact caacctgtac ttaactgaat tgactacagt 6480
atttgggccg caaatcactt cccctgcctt aactcagctg actatccagg cgctttacaa 6540
tctagctggt gggaatatgg attacttgtt aactaagtta ggtgtgggga ataaccaact 6600
cagctcatta attagtagtg gcctgatcac cggcaaccct attctgtatg actcacagac 6660
tcaactcttg ggtatacagg taatcctacc ctcagtcggg aatctaaata atatgcgtgc 6720
cacctatctg gaaaccttgt ctgtaagtac aactaaagga tttgcctcag ctcttgtccc 6780
aaaggtagtg acacaggtcg gttctgtgat agaagagctt gacacctcat actgtataga 6840
gaccgatttg gatctatatt gtacaagaat agtgacattc cctatgtctc ctggtattta 6900
ttcctgtttg agtggcaata catctgcttg catgtactca aagacagaag gcgcactcac 6960
tacgccgtat atgaccctca aaggctcagt tattgcaaac tgtaagatga caacatgtag 7020
gtgtgcagat cccccgggta tcatatcgca aaattatgga gaagctgtgt ctctaataga 7080
taggcaatca tgcaatatcc tatccttaga cgggataact ttgaggctca gtggggaatt 7140
cgatgcaact tatcaaagga atatctcaat acaagattct caagttatag tgacaggcaa 7200
tcttgatatc tcaactgagc ttgggaatgt caacaactcg ataagcaatg ctttggataa 7260
gttagaggaa agcaacagca aactagacaa ggtcaatgtc aaattggcca gcacatccgc 7320
tataattata gtaattatag taatattgtt agcattaatt gcagttggac tgcttctata 7380
ctgcaaggcc agaagcacac cagtcacatt aagtaaggat caactgagtg gtataaataa 7440
tattgcattt agtaactgaa taaaaatagc acctaatcat attcttacaa tggttcgcta 7500
tttgaccata gataacccat ctatcattag attatcctaa aatttgaact tcatcacaac 7560
tttcatctat aaaccatctc acttacactt tttaagtaga tttctatttt atagttatat 7620
aaaacagggc ccattgaata ccaaattaac ttactatttg taaaaatgag aattggggca 7680
aatatgtcac gaaggaatcc ttgcaaattc gaaattcgag gtcattgctt gaatggtaaa 7740
aggtgtcatt ttagtcataa ttattttgaa tggccacccc atgcactgct tgtaagacaa 7800
aactttatgt taaacagaat acttaagtct atggataaaa gcatagatac tttgtcagaa 7860
ataagtggag ctgcagagtt ggacagaaca gaagagtatg ccctcggtgt agttggagtg 7920
ctagagagtt atataggatc aataaataat ataactaaac aatcagcatg tgttgccatg 7980
agcaaactcc ttactgaact caacagcgat gacatcaaaa aactaaggga caatgaagag 8040
ccaaactcac ccaaagtaag agtgtacaat actgtcatat catatattga aagcaacagg 8100
aagaacaata aacaaactat ccatctgtta aaaagattgc cagcagacgt attgaagaaa 8160
accatcaaaa acacattgga tatccacaag agcataacca tcaataaccc aaaagaatca 8220
actgttagtg atacgaacga ccatgccaaa aataatgata ctacctgaca aatatccttg 8280
tagtataaat tccatactaa taacaagtaa ttgtagagtc actatgtata atcaaaaaaa 8340
cacactatat atcaatcaaa acaaccaaaa tagccatata tacccaccgg atcaaccatt 8400
caatgaaatc cattggacct ctcaagactt gattgatgca actcaaaatt ttctacaaca 8460
tctaggtatt actgatgata tatacacaat atatatatta gtgtcataat actcaatcct 8520
aatacttacc acatcatcaa attattaact caaacaattc aagctatggg acaaaatgga 8580
tcccattatt agtggaaatt ctgctaatgt ttatctaact gatagttatt taaaaggtgt 8640
tatttctttc tcagaatgta acgctttagg aagttacata ttcaatggtc cttatctcaa 8700
aaatgattat accaacttaa ttagtagaca aaatccatta atagaacaca taaatctaaa 8760
gaaactaaat ataacacagt ccttaatatc taagtatcat aaaggtgaaa taaaaataga 8820
agaacctact tactttcagt cattacttat gacatacaag agtatgacct cttcagaaca 8880
gactactact actaatttac ttaaaaagat aataagaaga gctatagaaa tcagtgatgt 8940
caaagtctat gctatattga ataaactggg gctcaaagaa aaagacaaga ttaaatccaa 9000
taatggacaa gatgaagaca actcagtcat tactaccata atcaaagatg atatactttt 9060
agctgtcaag gataatcaat ctcatcttaa agcagacaaa aatcaatcca caaaacaaaa 9120
agatacaatc aaaacaacac ttttgaagaa attaatgtgt tcgatgcaac atcctccatc 9180
atggttaata cattggttta atttatacac aaaattaaac agcatattaa cacaatatcg 9240
atctagtgag gtaaaaaacc atggttttat attgatagat aatcatactc ttagtggatt 9300
ccaatttatt ttgaatcaat atggttgtat agtttatcat aaggaactca aaagaattac 9360
tgtgacaact tataatcaat tcttgacatg gaaagatatt agccttagta gattaaatgt 9420
ttgtttgatt acatggatta gtaactgttt gaacacatta aacaaaagct taggcttaag 9480
atgtggattc aataatgtta tcttgacaca attattcctt tatggagatt gtatactaaa 9540
actattccac aatgaggggt tctacataat aaaagaggta gagggattta ttatgtctct 9600
aattttaaat ataacagaag aagatcaatt cagaaaacgg ttttataata gtatgctcaa 9660
caacatcaca gatgccgcca acaaagctca aaaaaatctg ctatcaagag tatgtcatac 9720
attattagat aagacaatat cagataatat aataaatggc agatggataa ttctattgag 9780
taagttccta aaattaatta agcttgcagg tgacaataac ctcaacaatc tgagtgaatt 9840
atattttttg ttcagaatat ttggacaccc aatggtagat gaaagacaag ccatggatgc 9900
tgttaaagtt aattgcaacg agaccaaatt ttatttgtta agtagtttga gtatgttaag 9960
aggagctttt atatatagaa ttataaaagg gtttgtaaat aattacaaca gatggcctac 10020
tttaagaaat gccattgtct tacccttaag atggttaact tactataaac taaacactta 10080
tccttccttg ttggaactta cagaaagaga tttgattgtt ctatcaggac tacgtttcta 10140
tcgagagttt cggttgccta aaaaagtgga tcttgaaatg atcataaatg ataaggctat 10200
atcacctcct aaaaatttaa tatggactag tttccctaga aattatatgc cgtcacacat 10260
acaaaattat atagaacatg aaaaattaaa attctctgat agtgataaat caagaagagt 10320
attagagtat tatttaagag ataacaaatt caatgaatgt gatttacaca actgtgtagt 10380
taatcaaagt tatcttaaca acccgaatca tgtggtatca ttgacaggca aagaaagaga 10440
actcagtgta ggtagaatgt ttgcaatgca accaggaatg ttcagacaag ttcaaatatt 10500
agcagagaaa atgatagcag aaaacatatt acaatttttc cctgaaagtc ttacaagata 10560
tggtgatcta gaactacaga aaatattaga attgaaagca ggaataagta acaaatcaaa 10620
tcgttacaat gataattaca acaattacat tagtaagtgc tctatcatca cagatctcag 10680
caaattcaat caagcatttc gatatgaaac atcatgtatt tgtagtgatg tactggatga 10740
actgcatggt gtacaatctc tattttcctg gttacattta actattcctc atgtcacaat 10800
aatatgcaca tataggcatg caccccccta tataaaggat catattgtag atcttaacaa 10860
tgtagatgag caaagtggac tatatagata tcatatgggt ggtatcgaag ggtggtgtca 10920
aaaactatgg accatagaag ctatatcact attagatcta atatctctca aagggaaatt 10980
ctcaattact gctttaatta atggtgacaa tcaatcaata gatataagta aaccagtcag 11040
actcatggaa ggtcaaactc atgctcaagc agattatttg ctagcattaa atagtctcaa 11100
attactgtat aaagagtatg caggaatagg ccacaaatta aaaggaactg agacttatat 11160
atcgagagat atgcaattta tgagtaaaac gatccaacat aacggtgtat attacccagc 11220
tagtataaag aaagtcctaa gagtgggacc gtggataaac actatacttg atgacttcaa 11280
agtgagtcta gaatctatag gtagtttgac acaagaatta gaatatagag gtgaaagtct 11340
attatgcagt ttaatattta gaaatgtatg gttatataat caaattgcat tacaacttaa 11400
aaatcatgca ttatgtaaca acaaattata tttggatata ttaaaagttc taaaacactt 11460
aaaaaccttt tttaatcttg ataacattga tacagcatta acattgtata tgaatttgcc 11520
catgttattt ggtggtggtg atcccaactt gttatatcga agtttctata gaagaactcc 11580
tgatttcctc acagaggcta tagttcactc tgtgttcata cttagttatt atacaaacca 11640
tgatttaaaa gataaacttc aagatctgtc agatgataga ttgaataagt tcttaacatg 11700
cataatcacg tttgataaaa accccaatgc tgaattcgtt acattgatga gagatcctca 11760
agctttagga tctgagaggc aagctaaaat tactagcgaa atcaatagac tggcagttac 11820
cgaggttttg agcacagctc caaacaaaat attttccaaa agtgcacaac actataccac 11880
tacagagata gatcttaatg atattatgca aaatatagaa cctacatatc ctcacgggct 11940
aagagttgtt tatgagagtt taccctttta taaagcagag aaaatagtaa atcttatatc 12000
cggtacaaaa tctataacta acatactgga aaagacttct gccatagact taacagatat 12060
tgatagagcc actgagatga tgaggaaaaa cataactttg cttataagga tattaccatt 12120
agattgtaac agagataaaa gagaaatatt gagtatggaa aacctaagta ttactgaatt 12180
aagcaaatac gttagagaaa gatcttggtc tttatccaat atagttggtg ttacatcacc 12240
cagtatcatg tatacaatgg acataaaata tacaacaagc actatagcta gtggcataat 12300
catagagaaa tataatgtca acagtttaac acgtggtgag agaggaccca ctaaaccatg 12360
ggttggttca tctacacaag agaaaaagac aatgccagtt tataatagac aagttttaac 12420
caaaaaacag agagatcaaa tagatctatt agcaaaattg gattgggtgt atgcatctat 12480
agataacaag gatgaattta tggaggaact tagcatagga actcttgggt taacatatga 12540
gaaggccaaa aaattattcc cacaatattt gagtgttaac tatttgcatc gtcttacagt 12600
cagtagtaga ccatgtgaat tccctgcatc tataccagct tatagaacta caaattatca 12660
ctttgatact agccctatta atcgcatatt aacagaaaag tatggtgatg aagatattga 12720
tatagtattc caaaactgta taagctttgg ccttagctta atgtctgtag tagaacaatt 12780
tactaatgta tgtcctaaca gaattattct catacccaag cttaatgaga tacatttgat 12840
gaaacctccc atattcacag gcgatgttga tattcacaag ttaaaacaag tgatacaaaa 12900
acaacatatg tttttaccag acaaaataag tttgactcaa tatgtggaat tattcttaag 12960
taataaaaca ctcaaatctg gatctaatgt taattctaat ttaatattgg cgcataagat 13020
atctgactat tttcataata cttacatttt gagtactaat ttagctggac attggattct 13080
tattatacaa cttatgaaag attctaaggg tatttttgaa aaagattggg gagagggata 13140
tataactgat catatgttca ttaatttgaa agttttcttc aatgcttata agacatatct 13200
cttgtgtttt cataaaggtt acggcagagc aaagctggag tgtgatatga atacttcaga 13260
tctcctatgt gtattggaat taatagacag tagttattgg aagtctatgt ctaaggtgtt 13320
tttagaacaa aaagttatca aatacattct tagccaggat gcaagtttac atagagtaaa 13380
aggatgtcat agcttcaaac tatggtttct taaacgtctt aatgtagcag aattcacagt 13440
ttgcccttgg gttgttaaca tagattatca tccaacacat atgaaagcaa tattaactta 13500
tattgatctt gttagaatgg gattgataaa tatagataga atatacatta aaaataaaca 13560
caagttcaat gatgagtttt atacttctaa tctgttttac attaattata acttctcaga 13620
taatactcat ctattaacta aacatataag gattgctaat tccgaattag aaagtaatta 13680
caacaaatta tatcatccta caccagaaac cctagaaaat atactaacca atccggttaa 13740
aagtaatgag aaaaagacac tgagtgacta ttgtataggt aaaaatgttg actcaataat 13800
gttaccatcg ttatctaata agaagcttat taaatcgtct acaatgatta gaaccaatta 13860
cagcagacaa gatttgtata atttatttcc tacggttgtg attgataaaa ttatagatca 13920
ttcaggtaat acagccaaat ctaaccaact ttacactact acttctcatc aaatatcctt 13980
agtgcacaat agcacatcac tttattgcat gcttccttgg catcatatta atagattcaa 14040
ttttgtattt agttctacag gttgtaaaat tagtatagag tatattttaa aagatcttaa 14100
aattaaggat cctaattgta tagcattcat aggtgaagga gcagggaatt tattattgcg 14160
tacagtagtg gaacttcatc ctgatataag atatatttac agaagtctga aagattgcaa 14220
tgatcatagt ttaccaattg agtttttaag gctgtacaat ggacatatca acattgatta 14280
tggtgaaaat ttgaccattc ctgctacaga tgcaaccaac aacattcatt ggtcttattt 14340
acatataaag tttgctgaac ctatcagtct ttttgtctgt gatgctgaat tgcctgtaac 14400
agtcaactgg agtaagatta taatagagtg gagcaagcat gtaagaaaat gcaagtactg 14460
ttcttcagtt aataaatgta cattgatagt aaaatatcat gctcaagatg atatcgattt 14520
caaattagac aacataacta tattaaaaac ttatgtatgc ttaggtagta agttaaaggg 14580
atctgaagtt tacttagtcc ttacaatagg tcctgcaaat gtgttcccag tatttaatgt 14640
agtacaaaat gctaaattga tactatcaag aactaaaaat ttcatcatgc ctaaaaaagc 14700
tgataaagag tctattgatg caaatattaa gagtttgata ccctttcttt gttaccctat 14760
aacaaaaaaa ggaattaata ctgcattgtc taaattaaag agtgttgtta gtggagatat 14820
actatcatat tctatagctg gacgtaatga agttttcagc aataaactta taaatcataa 14880
gcatatgaac atcttaaagt ggttcaatca tgttttaaat ttcagatcaa cagaattaaa 14940
ctataatcat ttatatatgg tagaatctac ttatcctcat ctaagtgaat tgttaaacag 15000
cttgacaacc aatgaactta aaaaactgat taaaatcaca ggtagtttgt tatacaactt 15060
ttataatgaa taatgagcaa aaatcttata acaaaaatag ctacacacta acattgtatt 15120
caattatagt tattgaaaat taataattat ataattttta ataacttcta gtgaactaat 15180
cctaaaatta tcattttgat ctaggaagaa taagtttaaa tccaaatcta attggtttat 15240
atgtatatta actaaattac gagatattag tttttgacac tttttttctc gtggccggca 15300
tggtcccagc ctcctcgctg gcgccggctg ggcaacatgc ttcggcatgg cgaatgggac 15360
tagcataacc ccttggggcc tctaaacggg tcttgagggg ttttttg 15407
<210> 6
<211> 17208
<212> DNA
<213> Artificial Sequence
<220>
<223> cRSVA_MVF_A
<400> 6
taatacgact cactataggt tttttcgcgt ctgatgaggc cgttaggccg aaactcctct 60
ccggagtcac gcgaaaaaat gcgtacaaca aacttgcgta aaccaaaaaa atggggcaaa 120
taagaatttg ataagtacca cttaaattta actcctttgg ttagaggcgc gccatgggca 180
gcaactcatt gagtatgata aaagttagat tgcaaaatct gtttgacaat gatgaagtag 240
cattgttaaa aataacatgc tatactgaca aattaataca gttaactaat gctttggcta 300
aggcagttat acatacaatc aaattgaatg gcattgtatt tgtgcatgtt attacaagta 360
gtgatatttg ccctaataat aatattgtag tgaaatccaa tttcacaaca atgccagtat 420
tacaaaatgg aggttatata tgggaaatga tggaattaac acactgctct caacctaatg 480
gcctaataga tgacaattgt gaaattaaat tctccaaaaa actaagtgat tcaacaatga 540
ccaattatat gaatcaatta tctgaattac ttggatttga cctcaatcca taaatcataa 600
taaatatcaa ctagcaaatc aatgtcacta acaccattag ttaatataaa acttgacaga 660
agataaaaat ggggcaaata aatcaattca gccgacccaa ccatggacac aacacacaat 720
gataccacac cacaaagact gatgatcaca gacatgaggc cattatcgct tgagactata 780
ataacatctc taaccagaga tatcataaca cataaattta tatacttgat aaatcatgaa 840
tgcatagtaa gaaaacttga tgaaagacag gccacattta catttctggt caactatgaa 900
atgaaactat tgcacaaagt gggaagcact aaatataaaa aatatactga atacaacaca 960
aaatatggca ctttccctat gccaatattt atcaatcatg atgggttctt agaatgcatt 1020
ggcattaagc ctaccaagca cacacccata atatacaagt atgatctcaa tccatgaata 1080
tcaaaccaag attcaaacaa tccgaaataa caactttatg cataatcaca ctccatagtc 1140
caaatggagc ctgaaaatta tagttattta aaattcctgc aggaaggaga gacataagat 1200
gaaagatggg gcaaatacaa aaatggctct tagcaaagtc aagttgaatg atacactcaa 1260
caaagatcaa cttctatcat ccagcaaata taccatccaa cggagcacag gagacagcat 1320
tgacactcct aattatgatg tgcagaaaca cattaataag ttatgtggca tgttattaat 1380
cacagaagat gctaatcata aattcactgg gttaataggt atgttatatg ctatgtctag 1440
attaggaaga gaagacacca taaaaatact caaagatgcg ggatatcatg ttaaggcaaa 1500
tggagtggat gtaacaacac atcgtcaaga cattaatggg aaagaaatga aatttgaagt 1560
gttaacatta gcaagcttaa caactgaaat tcaaatcaac attgagatag aatctagaaa 1620
atcctacaaa aaaatgctaa aagaaatggg agaggtggct ccagaataca ggcatgactc 1680
tcctgattgt gggatgataa tattatgtat agcggcatta gtaataacca aattagcagc 1740
aggagataga tcaggtctta cagctgtgat taggagagct aataatgtcc taaaaaatga 1800
aatgaaacgt tataaaggtt tattacccaa ggatatagcc aacagcttct atgaagtgtt 1860
tgaaaaatat cctcacttta tagatgtttt tgttcatttt ggtatagcac aatcttctac 1920
cagaggtggc agtagagttg aagggatttt tgcaggattg tttatgaatg cctatggtgc 1980
agggcaagtg atgttacggt ggggggtctt agcaaaatca gttaaaaaca ttatgttagg 2040
acacgctagt gtacaagcag aaatggaaca agttgtggag gtgtatgagt atgctcagaa 2100
attgggtgga gaagcaggat tctaccatat attgaacaac ccaaaagcat cactattatc 2160
tttgactcaa tttcctcact tctctagtgt agtattgggc aatgctgctg gcctaggcat 2220
aatgggagaa tacagaggta caccaaggaa tcaagattta tatgatgctg caaaagcata 2280
tgctgaacaa ctcaaagaaa atggtgtgat taactacagt gtattagatt tgacagcaga 2340
agaactagag gctatcaaac atcagcttaa tccaaaagat aatgatgtag agctttgagt 2400
taataaaaaa gtggggcaaa taaatcatca tggaaaagtt tgctcctgaa ttccatggag 2460
aagatgcaaa caacagagcc accaaattcc tagaatcaat aaagggcaaa ttcacatcac 2520
ccaaagatcc caagaaaaaa gatagtatca tatctgtcaa ctcaatagat atagaagtaa 2580
ccaaagaaag ccctataaca tcaaattcaa ccattataaa cccaataaat gagacagatg 2640
atactgtagg gaacaagccc aattatcaaa gaaagcctct agtaagtttc aaagaagacc 2700
ctacgccaag tgataatcct ttttcaaaac tatacaaaga aaccatagaa acatttgata 2760
acaatgaaga agaatctagc tattcatatg aagaaataaa tgatcagaca aacgataata 2820
taacagcaag attagatagg attgatgaga aattaagtga aatactagga atgcttcaca 2880
cattagtagt agcgagtgca ggacccacat ctgctcggga tggtataaga gatgccatgg 2940
ttggtttaag agaagaaatg atagaaaaaa tcagaactga agcattaatg accaatgaca 3000
gactagaagc tatggcaaga ctcaggaatg aagaaagtga aaagatggca aaagacacat 3060
cagatgaagt gtctctcaat ccaacatcag agaaactgaa caacctgttg gaagggaatg 3120
atagtgacaa tgatctatca cttgaagatt tctgattagc taccaaactg tacatcaaaa 3180
cacaacacca atagaaaacc aacaaacaaa ccaactcacc catccaacca aacatctatc 3240
tgctgattag ccaaccagcc aaaaaacaac cagccaatct aaaactagcc acccggaaaa 3300
aatcgatact atagttacaa aaaaagatgg ggcaaatatg gaaacatacg tgaataaact 3360
tcacgagggc tccacataca cagctgctgt tcaatacaat gtcctagaaa aagacgatga 3420
tcctgcatca cttacaatat gggtgcccat gttccaatca tccatgccag cagatctact 3480
cataaaagaa ctagccaatg tcaatatact agtgaaacaa atatccacac ccaagggacc 3540
ctcattaaga gtcatgataa actcaagaag tgcagtgcta gcacaaatgc ccagcaaatt 3600
taccatatgt gccaatgtgt ccttggatga aagaagcaag ctggcatatg atgtaaccac 3660
accctgtgaa attaaggcat gcagtctaac atgcctaaaa tcaaaaaata tgttaactac 3720
agttaaagat ctcactatga aaacactcaa cccaacacat gacatcattg ctttatgtga 3780
atttgaaaat atagtaacat caaaaaaagt cataatacca acatacctaa gatctatcag 3840
cgtcagaaat aaagatctga acacacttga aaatataaca accactgaat tcaaaaatgc 3900
cattacaaat gcaaaaatca tcccttactc aggattattg ttagtcatca cagtgactga 3960
caacaaagga gcattcaaat acataaagcc acaaagtcaa ttcatagtag atcttggagc 4020
ttacctagaa aaagaaagta tatattatgt tacaacaaat tggaagcaca cagctacacg 4080
atttgcaatc aaacccatgg aagattaacc tttttcctct acatcaatga gtagattcat 4140
acaaactttc taactacatt cttcacttca caatcataat caccaaccct ctgtggttca 4200
atcaatcaaa caaaactcat caagagttcc agatcatccc aagtcattgt tcatcagatc 4260
cagtactcaa ataagttaat aaaaaatcca catggggcaa ataatcattg agggaaatcc 4320
aactaatcac aacatctgtc aacatagaca agtcaacacg ctagataaaa tcaaccaatg 4380
gaaaatacat ccataactat agaattctca agcaaattct ggccttactt tacactaata 4440
cacatgataa caacaataat ctctttgata atcataatct ccatcatgat tgcaatacta 4500
aacaaactct gcgaatataa tgtattccat aacaaaacct ttgagctacc aagagctcga 4560
gtcaatacat agcattcacc aatctgatag ctcaaaacag taaccttgca tttgtaaatg 4620
aactaccctc acttcttcac aaaaccacat caacatctca ccatgcaagc catcatctat 4680
accataaagt agttaattaa aaatggccgg ccagtcataa caatgaacta ggatattaag 4740
accaaaaaca acgctggggc aaatgcaaac atgtccaaaa ccgaggacca acgcaccgcc 4800
aagacactag aaaggacctg ggacactttt aatcatctat tattcatatc atcgtgctta 4860
tacaagttaa atcttaaatc tatagcacaa atcacattat ctattttggc aattataatc 4920
tcaacctcac ttataattgc agccatcata ttcatagcct cggcaaacca caaagtcaca 4980
ctaacaactg caatcataca agatgcaacg aaccagatca agaacacaac cccaacatac 5040
ctcacccaga atccccagca tggaatcagc ttctccaatc tgtccggaac tacatcacaa 5100
tccaccacca tactagcttc aacaacacca agtgctgatt caaccccaca atccacaaca 5160
gtcaagatca aaaacacaac aacaacccaa atattaccta gcaaacccac cacaaaacaa 5220
cgccaaaata aaccacaaaa caaacccaac aatgattttc actttgaagt gttcaatttt 5280
gtaccctgca gcatatgcag caacaatcca acctgctggg ccatctgcaa gagaatacca 5340
aacaaaaaac ctggaaagaa aaccaccacc aagcccacaa aaaaaccaac cctcaagaca 5400
accaaaaaag atcccaaatc ccaaaccaca aaaccaaagg aagtactcac taccaagcct 5460
acaggaaagc caaccatcaa caccactaaa acaaacatca gaactacact gctcacctcc 5520
aacaccaaag gaaatccaga acacacaagt caagaggaaa ccctccactc aaccacctcc 5580
gaaggctatc caagcccatc acaagtccac acaacatccg gtcaagagga aaccctccac 5640
tcaaccacct ccgaaggcta tccaagccca tcacaagtct acacaacatc cgagtaccta 5700
tcacaatctc tatcttcatc caacacaaca aaatgatagt cattaaaaag cacgcgtgta 5760
ttgttgcaaa aagccatgac caaatcaaac agaatcaaaa tcaactctgg ggcaaataac 5820
aatgtccatc atgggtctca aggtgaacgt ctctgccata ttcatggcag tactgttaac 5880
tctccaaaca cccaccggtc aaatccattg gggcaatctc tctaagatag gggtggtagg 5940
aataggaagt gcaagctaca aagttatgac tcgttccagc catcaatcat tagtcataaa 6000
attaatgccc aatataactc tcctcaataa ctgcacgagg gtagagattg cagaatacag 6060
gagactactg agaacagttt tggaaccaat tagagatgca cttaatgcaa tgacccagaa 6120
tataagaccg gttcagagtg tagcttcaag taggagacac aagagatttg cgggagtagt 6180
cctggcaggt gcggccctag gcgttgccac agctgctcag ataacagccg gcattgcact 6240
tcaccagtcc atgctgaact ctcaagccat cgacaatctg agagcgagcc tggaaactac 6300
taatcaggca attgagacaa tcagacaagc agggcaggag atgatattgg ctgttcaggg 6360
tgtccaagac tacatcaata atgagctgat accgtctatg aaccaactat cttgtgattt 6420
aatcggccag aagctcgggc tcaaattgct cagatactat acagaaatcc tgtcattatt 6480
tggccccagt ttacgggacc ccatatctgc ggagatatct atccaggctt tgagctatgc 6540
gcttggagga gacatcaata aggtgttaga aaagctcgga tacagtggag gtgatttact 6600
gggcatctta gagagcggag gaataaaggc ccggataact cacgtcgaca cagagtccta 6660
cttcattgtc ctcagtatag cctatccgac gctgtccgag attaaggggg tgattgtcca 6720
ccggctagag ggggtctcgt acaacatagg ctctcaagag tggtatacca ctgtgcccaa 6780
gtatgttgca acccaagggt accttatctc gaattttgat gagtcatcgt gtactttcat 6840
gccagagggg actgtgtgca gccaaaatgc cttgtacccg atgagtcctc tgctccaaga 6900
atgcctccgg gggtacacca agtcctgtgc tcgtacactc gtatccgggt cttttgggaa 6960
ccggttcatt ttatcacaag ggaacctaat agccaattgt gcatcaatcc tttgcaagtg 7020
ttacacaaca ggaacgatca ttaatcaaga ccctgacaag atcctaacat acattgctgc 7080
cgatcactgc ccggtagtcg aggtgaacgg cgtgaccatc caagtcggga gcaggaggta 7140
tccagacgct gtgtacttgc acagaattga cctcggtcct cccatatcat tggagaggtt 7200
ggacgtaggg acaaatctgg ggaatgcaat tgctaagttg gaggatgcca aggaattgtt 7260
ggagtcatcg gaccagatat tgaggagtat gaaaggttta tcgagcacta gcataattat 7320
agtaattata gtaatattgt tagcattaat tgcagttgga ctgcttctat actgcaaggc 7380
cagaagcaca ccagtcacat taagtaagga tcaactgagt ggtataaata atattgcatt 7440
tagtaactga tagtcattaa aaagcacgcg tgtattgttg caaaaagcca tgaccaaatc 7500
aaacagaatc aaaatcaact ctggggcaaa taacaatgga gttgccaatc ctcaaaacaa 7560
atgctattac cacaatcctt gctgcagtca cactctgttt cgcttccagt caaaacatca 7620
ctgaagaatt ttatcaatca acatgcagtg cagtcagcaa aggctatctt agtgctctaa 7680
gaactggttg gtatactagt gttataacta tagaattaag taatatcaag gaaaataagt 7740
gtaatggtac agacgctaag gtaaaattaa taaaacaaga attagataaa tataaaaatg 7800
ctgtaacaga attgcagttg ctcatgcaaa gcacaccagc agccaacaat cgagccagaa 7860
gagaactacc aagatttatg aattatacac tcaacaatac caaaaacacc aatgtaacat 7920
taagtaagaa aaggaaaaga agatttcttg gatttttgtt aggtgttgga tctgcaatcg 7980
ccagtggcat tgccgtatcc aaggtcctgc acctagaagg ggaagtgaac aaaatcaaaa 8040
gtgctctact atccacaaac aaggctgtag tcagcttatc taatggagtc agtgtcttaa 8100
ccagcaaggt gttagacctc aaaaactata tagataaaca gttgttacct attgttaaca 8160
agcaaagctg cagcatatca aacattgaaa ctgtgataga gttccaacaa aagaacaaca 8220
gactactaga gattaccaga gaatttagtg ttaatgcagg tgtaactact cctgtaagca 8280
cttatatgtt aactaatagt gagttattat cattaatcaa tgatatgcct ataacaaatg 8340
atcagaaaaa gttaatgtcc agcaatgttc aaatagttag acagcaaagt tactctatca 8400
tgtcaataat aaaagaggaa gtcttggcat atgtagtaca attaccacta tatggtgtaa 8460
tagatactcc ttgttggaaa ctacacacat cccctttatg tacaaccaac acaaaggaag 8520
gatccaacat ctgcttaaca agaaccgaca gaggatggta ctgtgacaat gcaggatcag 8580
tatccttttt cccacaagct gaaacatgta aagttcaatc gaatcgggtg ttttgtgaca 8640
caatgaacag tttaacatta ccaagtgagg taaatctctg caacattgac atattcaacc 8700
ccaaatatga ttgcaaaatt atgacttcaa aaacagatgt aagcagctcc gttatcacat 8760
ctctaggagc cattgtgtca tgctatggca aaaccaaatg tacagcatcc aataaaaatc 8820
gtgggatcat aaagacattc tctaacgggt gtgattatgt atcaaataag ggggtggata 8880
ctgtgtctgt aggtaataca ttatattatg taaataagca agaaggcaaa agtctctatg 8940
taaaaggtga accaataata aatttctatg atccattagt gttcccctct gatgaatttg 9000
atgcatcaat atctcaagtc aatgagaaaa ttaatcagag tctagcattt atccgtaaat 9060
cagatgaatt attacataat gtaaatgctg gtaaatccac cacaaatatc atgataacta 9120
ccataattat agtaattata gtaatattgt tagcattaat tgcagttgga ctgcttctat 9180
actgcaaggc cagaagcaca ccagtcacat taagtaagga tcaactgagt ggtataaata 9240
atattgcatt tagtaactga ataaaaatag cacctaatca tattcttaca atggttcgct 9300
atttgaccat agataaccca tctatcatta gattatccta aaatttgaac ttcatcacaa 9360
ctttcatcta taaaccatct cacttacact ttttaagtag atttctattt tatagttata 9420
taaaacaggg cccattgaat accaaattaa cttactattt gtaaaaatga gaattggggc 9480
aaatatgtca cgaaggaatc cttgcaaatt cgaaattcga ggtcattgct tgaatggtaa 9540
aaggtgtcat tttagtcata attattttga atggccaccc catgcactgc ttgtaagaca 9600
aaactttatg ttaaacagaa tacttaagtc tatggataaa agcatagata ctttgtcaga 9660
aataagtgga gctgcagagt tggacagaac agaagagtat gccctcggtg tagttggagt 9720
gctagagagt tatataggat caataaataa tataactaaa caatcagcat gtgttgccat 9780
gagcaaactc cttactgaac tcaacagcga tgacatcaaa aaactaaggg acaatgaaga 9840
gccaaactca cccaaagtaa gagtgtacaa tactgtcata tcatatattg aaagcaacag 9900
gaagaacaat aaacaaacta tccatctgtt aaaaagattg ccagcagacg tattgaagaa 9960
aaccatcaaa aacacattgg atatccacaa gagcataacc atcaataacc caaaagaatc 10020
aactgttagt gatacgaacg accatgccaa aaataatgat actacctgac aaatatcctt 10080
gtagtataaa ttccatacta ataacaagta attgtagagt cactatgtat aatcaaaaaa 10140
acacactata tatcaatcaa aacaaccaaa atagccatat atacccaccg gatcaaccat 10200
tcaatgaaat ccattggacc tctcaagact tgattgatgc aactcaaaat tttctacaac 10260
atctaggtat tactgatgat atatacacaa tatatatatt agtgtcataa tactcaatcc 10320
taatacttac cacatcatca aattattaac tcaaacaatt caagctatgg gacaaaatgg 10380
atcccattat tagtggaaat tctgctaatg tttatctaac tgatagttat ttaaaaggtg 10440
ttatttcttt ctcagaatgt aacgctttag gaagttacat attcaatggt ccttatctca 10500
aaaatgatta taccaactta attagtagac aaaatccatt aatagaacac ataaatctaa 10560
agaaactaaa tataacacag tccttaatat ctaagtatca taaaggtgaa ataaaaatag 10620
aagaacctac ttactttcag tcattactta tgacatacaa gagtatgacc tcttcagaac 10680
agactactac tactaattta cttaaaaaga taataagaag agctatagaa atcagtgatg 10740
tcaaagtcta tgctatattg aataaactgg ggctcaaaga aaaagacaag attaaatcca 10800
ataatggaca agatgaagac aactcagtca ttactaccat aatcaaagat gatatacttt 10860
tagctgtcaa ggataatcaa tctcatctta aagcagacaa aaatcaatcc acaaaacaaa 10920
aagatacaat caaaacaaca cttttgaaga aattaatgtg ttcgatgcaa catcctccat 10980
catggttaat acattggttt aatttataca caaaattaaa cagcatatta acacaatatc 11040
gatctagtga ggtaaaaaac catggtttta tattgataga taatcatact cttagtggat 11100
tccaatttat tttgaatcaa tatggttgta tagtttatca taaggaactc aaaagaatta 11160
ctgtgacaac ttataatcaa ttcttgacat ggaaagatat tagccttagt agattaaatg 11220
tttgtttgat tacatggatt agtaactgtt tgaacacatt aaacaaaagc ttaggcttaa 11280
gatgtggatt caataatgtt atcttgacac aattattcct ttatggagat tgtatactaa 11340
aactattcca caatgagggg ttctacataa taaaagaggt agagggattt attatgtctc 11400
taattttaaa tataacagaa gaagatcaat tcagaaaacg gttttataat agtatgctca 11460
acaacatcac agatgccgcc aacaaagctc aaaaaaatct gctatcaaga gtatgtcata 11520
cattattaga taagacaata tcagataata taataaatgg cagatggata attctattga 11580
gtaagttcct aaaattaatt aagcttgcag gtgacaataa cctcaacaat ctgagtgaat 11640
tatatttttt gttcagaata tttggacacc caatggtaga tgaaagacaa gccatggatg 11700
ctgttaaagt taattgcaac gagaccaaat tttatttgtt aagtagtttg agtatgttaa 11760
gaggagcttt tatatataga attataaaag ggtttgtaaa taattacaac agatggccta 11820
ctttaagaaa tgccattgtc ttacccttaa gatggttaac ttactataaa ctaaacactt 11880
atccttcctt gttggaactt acagaaagag atttgattgt tctatcagga ctacgtttct 11940
atcgagagtt tcggttgcct aaaaaagtgg atcttgaaat gatcataaat gataaggcta 12000
tatcacctcc taaaaattta atatggacta gtttccctag aaattatatg ccgtcacaca 12060
tacaaaatta tatagaacat gaaaaattaa aattctctga tagtgataaa tcaagaagag 12120
tattagagta ttatttaaga gataacaaat tcaatgaatg tgatttacac aactgtgtag 12180
ttaatcaaag ttatcttaac aacccgaatc atgtggtatc attgacaggc aaagaaagag 12240
aactcagtgt aggtagaatg tttgcaatgc aaccaggaat gttcagacaa gttcaaatat 12300
tagcagagaa aatgatagca gaaaacatat tacaattttt ccctgaaagt cttacaagat 12360
atggtgatct agaactacag aaaatattag aattgaaagc aggaataagt aacaaatcaa 12420
atcgttacaa tgataattac aacaattaca ttagtaagtg ctctatcatc acagatctca 12480
gcaaattcaa tcaagcattt cgatatgaaa catcatgtat ttgtagtgat gtactggatg 12540
aactgcatgg tgtacaatct ctattttcct ggttacattt aactattcct catgtcacaa 12600
taatatgcac atataggcat gcacccccct atataaagga tcatattgta gatcttaaca 12660
atgtagatga gcaaagtgga ctatatagat atcatatggg tggtatcgaa gggtggtgtc 12720
aaaaactatg gaccatagaa gctatatcac tattagatct aatatctctc aaagggaaat 12780
tctcaattac tgctttaatt aatggtgaca atcaatcaat agatataagt aaaccagtca 12840
gactcatgga aggtcaaact catgctcaag cagattattt gctagcatta aatagtctca 12900
aattactgta taaagagtat gcaggaatag gccacaaatt aaaaggaact gagacttata 12960
tatcgagaga tatgcaattt atgagtaaaa cgatccaaca taacggtgta tattacccag 13020
ctagtataaa gaaagtccta agagtgggac cgtggataaa cactatactt gatgacttca 13080
aagtgagtct agaatctata ggtagtttga cacaagaatt agaatataga ggtgaaagtc 13140
tattatgcag tttaatattt agaaatgtat ggttatataa tcaaattgca ttacaactta 13200
aaaatcatgc attatgtaac aacaaattat atttggatat attaaaagtt ctaaaacact 13260
taaaaacctt ttttaatctt gataacattg atacagcatt aacattgtat atgaatttgc 13320
ccatgttatt tggtggtggt gatcccaact tgttatatcg aagtttctat agaagaactc 13380
ctgatttcct cacagaggct atagttcact ctgtgttcat acttagttat tatacaaacc 13440
atgatttaaa agataaactt caagatctgt cagatgatag attgaataag ttcttaacat 13500
gcataatcac gtttgataaa aaccccaatg ctgaattcgt tacattgatg agagatcctc 13560
aagctttagg atctgagagg caagctaaaa ttactagcga aatcaataga ctggcagtta 13620
ccgaggtttt gagcacagct ccaaacaaaa tattttccaa aagtgcacaa cactatacca 13680
ctacagagat agatcttaat gatattatgc aaaatataga acctacatat cctcacgggc 13740
taagagttgt ttatgagagt ttaccctttt ataaagcaga gaaaatagta aatcttatat 13800
ccggtacaaa atctataact aacatactgg aaaagacttc tgccatagac ttaacagata 13860
ttgatagagc cactgagatg atgaggaaaa acataacttt gcttataagg atattaccat 13920
tagattgtaa cagagataaa agagaaatat tgagtatgga aaacctaagt attactgaat 13980
taagcaaata cgttagagaa agatcttggt ctttatccaa tatagttggt gttacatcac 14040
ccagtatcat gtatacaatg gacataaaat atacaacaag cactatagct agtggcataa 14100
tcatagagaa atataatgtc aacagtttaa cacgtggtga gagaggaccc actaaaccat 14160
gggttggttc atctacacaa gagaaaaaga caatgccagt ttataataga caagttttaa 14220
ccaaaaaaca gagagatcaa atagatctat tagcaaaatt ggattgggtg tatgcatcta 14280
tagataacaa ggatgaattt atggaggaac ttagcatagg aactcttggg ttaacatatg 14340
agaaggccaa aaaattattc ccacaatatt tgagtgttaa ctatttgcat cgtcttacag 14400
tcagtagtag accatgtgaa ttccctgcat ctataccagc ttatagaact acaaattatc 14460
actttgatac tagccctatt aatcgcatat taacagaaaa gtatggtgat gaagatattg 14520
atatagtatt ccaaaactgt ataagctttg gccttagctt aatgtctgta gtagaacaat 14580
ttactaatgt atgtcctaac agaattattc tcatacccaa gcttaatgag atacatttga 14640
tgaaacctcc catattcaca ggcgatgttg atattcacaa gttaaaacaa gtgatacaaa 14700
aacaacatat gtttttacca gacaaaataa gtttgactca atatgtggaa ttattcttaa 14760
gtaataaaac actcaaatct ggatctaatg ttaattctaa tttaatattg gcgcataaga 14820
tatctgacta ttttcataat acttacattt tgagtactaa tttagctgga cattggattc 14880
ttattataca acttatgaaa gattctaagg gtatttttga aaaagattgg ggagagggat 14940
atataactga tcatatgttc attaatttga aagttttctt caatgcttat aagacatatc 15000
tcttgtgttt tcataaaggt tacggcagag caaagctgga gtgtgatatg aatacttcag 15060
atctcctatg tgtattggaa ttaatagaca gtagttattg gaagtctatg tctaaggtgt 15120
ttttagaaca aaaagttatc aaatacattc ttagccagga tgcaagttta catagagtaa 15180
aaggatgtca tagcttcaaa ctatggtttc ttaaacgtct taatgtagca gaattcacag 15240
tttgcccttg ggttgttaac atagattatc atccaacaca tatgaaagca atattaactt 15300
atattgatct tgttagaatg ggattgataa atatagatag aatatacatt aaaaataaac 15360
acaagttcaa tgatgagttt tatacttcta atctgtttta cattaattat aacttctcag 15420
ataatactca tctattaact aaacatataa ggattgctaa ttccgaatta gaaagtaatt 15480
acaacaaatt atatcatcct acaccagaaa ccctagaaaa tatactaacc aatccggtta 15540
aaagtaatga gaaaaagaca ctgagtgact attgtatagg taaaaatgtt gactcaataa 15600
tgttaccatc gttatctaat aagaagctta ttaaatcgtc tacaatgatt agaaccaatt 15660
acagcagaca agatttgtat aatttatttc ctacggttgt gattgataaa attatagatc 15720
attcaggtaa tacagccaaa tctaaccaac tttacactac tacttctcat caaatatcct 15780
tagtgcacaa tagcacatca ctttattgca tgcttccttg gcatcatatt aatagattca 15840
attttgtatt tagttctaca ggttgtaaaa ttagtataga gtatatttta aaagatctta 15900
aaattaagga tcctaattgt atagcattca taggtgaagg agcagggaat ttattattgc 15960
gtacagtagt ggaacttcat cctgatataa gatatattta cagaagtctg aaagattgca 16020
atgatcatag tttaccaatt gagtttttaa ggctgtacaa tggacatatc aacattgatt 16080
atggtgaaaa tttgaccatt cctgctacag atgcaaccaa caacattcat tggtcttatt 16140
tacatataaa gtttgctgaa cctatcagtc tttttgtctg tgatgctgaa ttgcctgtaa 16200
cagtcaactg gagtaagatt ataatagagt ggagcaagca tgtaagaaaa tgcaagtact 16260
gttcttcagt taataaatgt acattgatag taaaatatca tgctcaagat gatatcgatt 16320
tcaaattaga caacataact atattaaaaa cttatgtatg cttaggtagt aagttaaagg 16380
gatctgaagt ttacttagtc cttacaatag gtcctgcaaa tgtgttccca gtatttaatg 16440
tagtacaaaa tgctaaattg atactatcaa gaactaaaaa tttcatcatg cctaaaaaag 16500
ctgataaaga gtctattgat gcaaatatta agagtttgat accctttctt tgttacccta 16560
taacaaaaaa aggaattaat actgcattgt ctaaattaaa gagtgttgtt agtggagata 16620
tactatcata ttctatagct ggacgtaatg aagttttcag caataaactt ataaatcata 16680
agcatatgaa catcttaaag tggttcaatc atgttttaaa tttcagatca acagaattaa 16740
actataatca tttatatatg gtagaatcta cttatcctca tctaagtgaa ttgttaaaca 16800
gcttgacaac caatgaactt aaaaaactga ttaaaatcac aggtagtttg ttatacaact 16860
tttataatga ataatgagca aaaatcttat aacaaaaata gctacacact aacattgtat 16920
tcaattatag ttattgaaaa ttaataatta tataattttt aataacttct agtgaactaa 16980
tcctaaaatt atcattttga tctaggaaga ataagtttaa atccaaatct aattggttta 17040
tatgtatatt aactaaatta cgagatatta gtttttgaca ctttttttct cgtggccggc 17100
atggtcccag cctcctcgct ggcgccggct gggcaacatg cttcggcatg gcgaatggga 17160
ctagcataac cccttggggc ctctaaacgg gtcttgaggg gttttttg 17208
<210> 7
<211> 17217
<212> DNA
<213> Artificial Sequence
<220>
<223> cRSVA_NDVF_A
<400> 7
taatacgact cactataggt tttttcgcgt ctgatgaggc cgttaggccg aaactcctct 60
ccggagtcac gcgaaaaaat gcgtacaaca aacttgcgta aaccaaaaaa atggggcaaa 120
taagaatttg ataagtacca cttaaattta actcctttgg ttagaggcgc gccatgggca 180
gcaactcatt gagtatgata aaagttagat tgcaaaatct gtttgacaat gatgaagtag 240
cattgttaaa aataacatgc tatactgaca aattaataca gttaactaat gctttggcta 300
aggcagttat acatacaatc aaattgaatg gcattgtatt tgtgcatgtt attacaagta 360
gtgatatttg ccctaataat aatattgtag tgaaatccaa tttcacaaca atgccagtat 420
tacaaaatgg aggttatata tgggaaatga tggaattaac acactgctct caacctaatg 480
gcctaataga tgacaattgt gaaattaaat tctccaaaaa actaagtgat tcaacaatga 540
ccaattatat gaatcaatta tctgaattac ttggatttga cctcaatcca taaatcataa 600
taaatatcaa ctagcaaatc aatgtcacta acaccattag ttaatataaa acttgacaga 660
agataaaaat ggggcaaata aatcaattca gccgacccaa ccatggacac aacacacaat 720
gataccacac cacaaagact gatgatcaca gacatgaggc cattatcgct tgagactata 780
ataacatctc taaccagaga tatcataaca cataaattta tatacttgat aaatcatgaa 840
tgcatagtaa gaaaacttga tgaaagacag gccacattta catttctggt caactatgaa 900
atgaaactat tgcacaaagt gggaagcact aaatataaaa aatatactga atacaacaca 960
aaatatggca ctttccctat gccaatattt atcaatcatg atgggttctt agaatgcatt 1020
ggcattaagc ctaccaagca cacacccata atatacaagt atgatctcaa tccatgaata 1080
tcaaaccaag attcaaacaa tccgaaataa caactttatg cataatcaca ctccatagtc 1140
caaatggagc ctgaaaatta tagttattta aaattcctgc aggaaggaga gacataagat 1200
gaaagatggg gcaaatacaa aaatggctct tagcaaagtc aagttgaatg atacactcaa 1260
caaagatcaa cttctatcat ccagcaaata taccatccaa cggagcacag gagacagcat 1320
tgacactcct aattatgatg tgcagaaaca cattaataag ttatgtggca tgttattaat 1380
cacagaagat gctaatcata aattcactgg gttaataggt atgttatatg ctatgtctag 1440
attaggaaga gaagacacca taaaaatact caaagatgcg ggatatcatg ttaaggcaaa 1500
tggagtggat gtaacaacac atcgtcaaga cattaatggg aaagaaatga aatttgaagt 1560
gttaacatta gcaagcttaa caactgaaat tcaaatcaac attgagatag aatctagaaa 1620
atcctacaaa aaaatgctaa aagaaatggg agaggtggct ccagaataca ggcatgactc 1680
tcctgattgt gggatgataa tattatgtat agcggcatta gtaataacca aattagcagc 1740
aggagataga tcaggtctta cagctgtgat taggagagct aataatgtcc taaaaaatga 1800
aatgaaacgt tataaaggtt tattacccaa ggatatagcc aacagcttct atgaagtgtt 1860
tgaaaaatat cctcacttta tagatgtttt tgttcatttt ggtatagcac aatcttctac 1920
cagaggtggc agtagagttg aagggatttt tgcaggattg tttatgaatg cctatggtgc 1980
agggcaagtg atgttacggt ggggggtctt agcaaaatca gttaaaaaca ttatgttagg 2040
acacgctagt gtacaagcag aaatggaaca agttgtggag gtgtatgagt atgctcagaa 2100
attgggtgga gaagcaggat tctaccatat attgaacaac ccaaaagcat cactattatc 2160
tttgactcaa tttcctcact tctctagtgt agtattgggc aatgctgctg gcctaggcat 2220
aatgggagaa tacagaggta caccaaggaa tcaagattta tatgatgctg caaaagcata 2280
tgctgaacaa ctcaaagaaa atggtgtgat taactacagt gtattagatt tgacagcaga 2340
agaactagag gctatcaaac atcagcttaa tccaaaagat aatgatgtag agctttgagt 2400
taataaaaaa gtggggcaaa taaatcatca tggaaaagtt tgctcctgaa ttccatggag 2460
aagatgcaaa caacagagcc accaaattcc tagaatcaat aaagggcaaa ttcacatcac 2520
ccaaagatcc caagaaaaaa gatagtatca tatctgtcaa ctcaatagat atagaagtaa 2580
ccaaagaaag ccctataaca tcaaattcaa ccattataaa cccaataaat gagacagatg 2640
atactgtagg gaacaagccc aattatcaaa gaaagcctct agtaagtttc aaagaagacc 2700
ctacgccaag tgataatcct ttttcaaaac tatacaaaga aaccatagaa acatttgata 2760
acaatgaaga agaatctagc tattcatatg aagaaataaa tgatcagaca aacgataata 2820
taacagcaag attagatagg attgatgaga aattaagtga aatactagga atgcttcaca 2880
cattagtagt agcgagtgca ggacccacat ctgctcggga tggtataaga gatgccatgg 2940
ttggtttaag agaagaaatg atagaaaaaa tcagaactga agcattaatg accaatgaca 3000
gactagaagc tatggcaaga ctcaggaatg aagaaagtga aaagatggca aaagacacat 3060
cagatgaagt gtctctcaat ccaacatcag agaaactgaa caacctgttg gaagggaatg 3120
atagtgacaa tgatctatca cttgaagatt tctgattagc taccaaactg tacatcaaaa 3180
cacaacacca atagaaaacc aacaaacaaa ccaactcacc catccaacca aacatctatc 3240
tgctgattag ccaaccagcc aaaaaacaac cagccaatct aaaactagcc acccggaaaa 3300
aatcgatact atagttacaa aaaaagatgg ggcaaatatg gaaacatacg tgaataaact 3360
tcacgagggc tccacataca cagctgctgt tcaatacaat gtcctagaaa aagacgatga 3420
tcctgcatca cttacaatat gggtgcccat gttccaatca tccatgccag cagatctact 3480
cataaaagaa ctagccaatg tcaatatact agtgaaacaa atatccacac ccaagggacc 3540
ctcattaaga gtcatgataa actcaagaag tgcagtgcta gcacaaatgc ccagcaaatt 3600
taccatatgt gccaatgtgt ccttggatga aagaagcaag ctggcatatg atgtaaccac 3660
accctgtgaa attaaggcat gcagtctaac atgcctaaaa tcaaaaaata tgttaactac 3720
agttaaagat ctcactatga aaacactcaa cccaacacat gacatcattg ctttatgtga 3780
atttgaaaat atagtaacat caaaaaaagt cataatacca acatacctaa gatctatcag 3840
cgtcagaaat aaagatctga acacacttga aaatataaca accactgaat tcaaaaatgc 3900
cattacaaat gcaaaaatca tcccttactc aggattattg ttagtcatca cagtgactga 3960
caacaaagga gcattcaaat acataaagcc acaaagtcaa ttcatagtag atcttggagc 4020
ttacctagaa aaagaaagta tatattatgt tacaacaaat tggaagcaca cagctacacg 4080
atttgcaatc aaacccatgg aagattaacc tttttcctct acatcaatga gtagattcat 4140
acaaactttc taactacatt cttcacttca caatcataat caccaaccct ctgtggttca 4200
atcaatcaaa caaaactcat caagagttcc agatcatccc aagtcattgt tcatcagatc 4260
cagtactcaa ataagttaat aaaaaatcca catggggcaa ataatcattg agggaaatcc 4320
aactaatcac aacatctgtc aacatagaca agtcaacacg ctagataaaa tcaaccaatg 4380
gaaaatacat ccataactat agaattctca agcaaattct ggccttactt tacactaata 4440
cacatgataa caacaataat ctctttgata atcataatct ccatcatgat tgcaatacta 4500
aacaaactct gcgaatataa tgtattccat aacaaaacct ttgagctacc aagagctcga 4560
gtcaatacat agcattcacc aatctgatag ctcaaaacag taaccttgca tttgtaaatg 4620
aactaccctc acttcttcac aaaaccacat caacatctca ccatgcaagc catcatctat 4680
accataaagt agttaattaa aaatggccgg ccagtcataa caatgaacta ggatattaag 4740
accaaaaaca acgctggggc aaatgcaaac atgtccaaaa ccgaggacca acgcaccgcc 4800
aagacactag aaaggacctg ggacactttt aatcatctat tattcatatc atcgtgctta 4860
tacaagttaa atcttaaatc tatagcacaa atcacattat ctattttggc aattataatc 4920
tcaacctcac ttataattgc agccatcata ttcatagcct cggcaaacca caaagtcaca 4980
ctaacaactg caatcataca agatgcaacg aaccagatca agaacacaac cccaacatac 5040
ctcacccaga atccccagca tggaatcagc ttctccaatc tgtccggaac tacatcacaa 5100
tccaccacca tactagcttc aacaacacca agtgctgatt caaccccaca atccacaaca 5160
gtcaagatca aaaacacaac aacaacccaa atattaccta gcaaacccac cacaaaacaa 5220
cgccaaaata aaccacaaaa caaacccaac aatgattttc actttgaagt gttcaatttt 5280
gtaccctgca gcatatgcag caacaatcca acctgctggg ccatctgcaa gagaatacca 5340
aacaaaaaac ctggaaagaa aaccaccacc aagcccacaa aaaaaccaac cctcaagaca 5400
accaaaaaag atcccaaatc ccaaaccaca aaaccaaagg aagtactcac taccaagcct 5460
acaggaaagc caaccatcaa caccactaaa acaaacatca gaactacact gctcacctcc 5520
aacaccaaag gaaatccaga acacacaagt caagaggaaa ccctccactc aaccacctcc 5580
gaaggctatc caagcccatc acaagtccac acaacatccg gtcaagagga aaccctccac 5640
tcaaccacct ccgaaggcta tccaagccca tcacaagtct acacaacatc cgagtaccta 5700
tcacaatctc tatcttcatc caacacaaca aaatgatagt cattaaaaag cacgcgtgta 5760
ttgttgcaaa aagccatgac caaatcaaac agaatcaaaa tcaactctgg ggcaaataac 5820
aatgggttcc aagtcttcta ccaggttccc agtacctcta atgctgaccg tccgagtcat 5880
gctggcactg agttgcgtct gtccggccag cgcccttgat ggcaggcctc ttgcggctgc 5940
agggattgtg gtaacaggag acaaagcggt caacatatac acatcatctc agacagggtc 6000
aatcataatc aagttactcc cgaatatgcc caaggataaa gaggcgtgtg caaaagcacc 6060
gttggaggca tacaacagga cattgactac tttgctcacc cctcttggtg attctatccg 6120
taggatacaa gagtctgtga ccacgtccgg aggaagaaaa cagggacgcc ttataggagc 6180
cattatcggt ggtgtagctc tcggggtcgc gaccgctgca caaataacag cagcctcggc 6240
tttgatacaa gccaatcaaa atgctgccaa catcctccgg ctcaaagaga gcattgctgc 6300
aaccaatgag gctgtacacg aggtcactga cggattatca caactagcag tggcagttgg 6360
gaagatgcag caatttgtta atgaccagtt taataagaca gcccaggaat tggactgtat 6420
aaaaattgca cagcaagttg gtgtagaact caacctgtac ttaactgaat tgactacagt 6480
atttgggccg caaatcactt cccctgcctt aactcagctg actatccagg cgctttacaa 6540
tctagctggt gggaatatgg attacttgtt aactaagtta ggtgtgggga ataaccaact 6600
cagctcatta attagtagtg gcctgatcac cggcaaccct attctgtatg actcacagac 6660
tcaactcttg ggtatacagg taatcctacc ctcagtcggg aatctaaata atatgcgtgc 6720
cacctatctg gaaaccttgt ctgtaagtac aactaaagga tttgcctcag ctcttgtccc 6780
aaaggtagtg acacaggtcg gttctgtgat agaagagctt gacacctcat actgtataga 6840
gaccgatttg gatctatatt gtacaagaat agtgacattc cctatgtctc ctggtattta 6900
ttcctgtttg agtggcaata catctgcttg catgtactca aagacagaag gcgcactcac 6960
tacgccgtat atgaccctca aaggctcagt tattgcaaac tgtaagatga caacatgtag 7020
gtgtgcagat cccccgggta tcatatcgca aaattatgga gaagctgtgt ctctaataga 7080
taggcaatca tgcaatatcc tatccttaga cgggataact ttgaggctca gtggggaatt 7140
cgatgcaact tatcaaagga atatctcaat acaagattct caagttatag tgacaggcaa 7200
tcttgatatc tcaactgagc ttgggaatgt caacaactcg ataagcaatg ctttggataa 7260
gttagaggaa agcaacagca aactagacaa ggtcaatgtc aaattggcca gcacatccgc 7320
tataattata gtaattatag taatattgtt agcattaatt gcagttggac tgcttctata 7380
ctgcaaggcc agaagcacac cagtcacatt aagtaaggat caactgagtg gtataaataa 7440
tattgcattt agtaactgat agtcattaaa aagcacgcgt gtattgttgc aaaaagccat 7500
gaccaaatca aacagaatca aaatcaactc tggggcaaat aacaatggag ttgccaatcc 7560
tcaaaacaaa tgctattacc acaatccttg ctgcagtcac actctgtttc gcttccagtc 7620
aaaacatcac tgaagaattt tatcaatcaa catgcagtgc agtcagcaaa ggctatctta 7680
gtgctctaag aactggttgg tatactagtg ttataactat agaattaagt aatatcaagg 7740
aaaataagtg taatggtaca gacgctaagg taaaattaat aaaacaagaa ttagataaat 7800
ataaaaatgc tgtaacagaa ttgcagttgc tcatgcaaag cacaccagca gccaacaatc 7860
gagccagaag agaactacca agatttatga attatacact caacaatacc aaaaacacca 7920
atgtaacatt aagtaagaaa aggaaaagaa gatttcttgg atttttgtta ggtgttggat 7980
ctgcaatcgc cagtggcatt gccgtatcca aggtcctgca cctagaaggg gaagtgaaca 8040
aaatcaaaag tgctctacta tccacaaaca aggctgtagt cagcttatct aatggagtca 8100
gtgtcttaac cagcaaggtg ttagacctca aaaactatat agataaacag ttgttaccta 8160
ttgttaacaa gcaaagctgc agcatatcaa acattgaaac tgtgatagag ttccaacaaa 8220
agaacaacag actactagag attaccagag aatttagtgt taatgcaggt gtaactactc 8280
ctgtaagcac ttatatgtta actaatagtg agttattatc attaatcaat gatatgccta 8340
taacaaatga tcagaaaaag ttaatgtcca gcaatgttca aatagttaga cagcaaagtt 8400
actctatcat gtcaataata aaagaggaag tcttggcata tgtagtacaa ttaccactat 8460
atggtgtaat agatactcct tgttggaaac tacacacatc ccctttatgt acaaccaaca 8520
caaaggaagg atccaacatc tgcttaacaa gaaccgacag aggatggtac tgtgacaatg 8580
caggatcagt atcctttttc ccacaagctg aaacatgtaa agttcaatcg aatcgggtgt 8640
tttgtgacac aatgaacagt ttaacattac caagtgaggt aaatctctgc aacattgaca 8700
tattcaaccc caaatatgat tgcaaaatta tgacttcaaa aacagatgta agcagctccg 8760
ttatcacatc tctaggagcc attgtgtcat gctatggcaa aaccaaatgt acagcatcca 8820
ataaaaatcg tgggatcata aagacattct ctaacgggtg tgattatgta tcaaataagg 8880
gggtggatac tgtgtctgta ggtaatacat tatattatgt aaataagcaa gaaggcaaaa 8940
gtctctatgt aaaaggtgaa ccaataataa atttctatga tccattagtg ttcccctctg 9000
atgaatttga tgcatcaata tctcaagtca atgagaaaat taatcagagt ctagcattta 9060
tccgtaaatc agatgaatta ttacataatg taaatgctgg taaatccacc acaaatatca 9120
tgataactac cataattata gtaattatag taatattgtt agcattaatt gcagttggac 9180
tgcttctata ctgcaaggcc agaagcacac cagtcacatt aagtaaggat caactgagtg 9240
gtataaataa tattgcattt agtaactgaa taaaaatagc acctaatcat attcttacaa 9300
tggttcgcta tttgaccata gataacccat ctatcattag attatcctaa aatttgaact 9360
tcatcacaac tttcatctat aaaccatctc acttacactt tttaagtaga tttctatttt 9420
atagttatat aaaacagggc ccattgaata ccaaattaac ttactatttg taaaaatgag 9480
aattggggca aatatgtcac gaaggaatcc ttgcaaattc gaaattcgag gtcattgctt 9540
gaatggtaaa aggtgtcatt ttagtcataa ttattttgaa tggccacccc atgcactgct 9600
tgtaagacaa aactttatgt taaacagaat acttaagtct atggataaaa gcatagatac 9660
tttgtcagaa ataagtggag ctgcagagtt ggacagaaca gaagagtatg ccctcggtgt 9720
agttggagtg ctagagagtt atataggatc aataaataat ataactaaac aatcagcatg 9780
tgttgccatg agcaaactcc ttactgaact caacagcgat gacatcaaaa aactaaggga 9840
caatgaagag ccaaactcac ccaaagtaag agtgtacaat actgtcatat catatattga 9900
aagcaacagg aagaacaata aacaaactat ccatctgtta aaaagattgc cagcagacgt 9960
attgaagaaa accatcaaaa acacattgga tatccacaag agcataacca tcaataaccc 10020
aaaagaatca actgttagtg atacgaacga ccatgccaaa aataatgata ctacctgaca 10080
aatatccttg tagtataaat tccatactaa taacaagtaa ttgtagagtc actatgtata 10140
atcaaaaaaa cacactatat atcaatcaaa acaaccaaaa tagccatata tacccaccgg 10200
atcaaccatt caatgaaatc cattggacct ctcaagactt gattgatgca actcaaaatt 10260
ttctacaaca tctaggtatt actgatgata tatacacaat atatatatta gtgtcataat 10320
actcaatcct aatacttacc acatcatcaa attattaact caaacaattc aagctatggg 10380
acaaaatgga tcccattatt agtggaaatt ctgctaatgt ttatctaact gatagttatt 10440
taaaaggtgt tatttctttc tcagaatgta acgctttagg aagttacata ttcaatggtc 10500
cttatctcaa aaatgattat accaacttaa ttagtagaca aaatccatta atagaacaca 10560
taaatctaaa gaaactaaat ataacacagt ccttaatatc taagtatcat aaaggtgaaa 10620
taaaaataga agaacctact tactttcagt cattacttat gacatacaag agtatgacct 10680
cttcagaaca gactactact actaatttac ttaaaaagat aataagaaga gctatagaaa 10740
tcagtgatgt caaagtctat gctatattga ataaactggg gctcaaagaa aaagacaaga 10800
ttaaatccaa taatggacaa gatgaagaca actcagtcat tactaccata atcaaagatg 10860
atatactttt agctgtcaag gataatcaat ctcatcttaa agcagacaaa aatcaatcca 10920
caaaacaaaa agatacaatc aaaacaacac ttttgaagaa attaatgtgt tcgatgcaac 10980
atcctccatc atggttaata cattggttta atttatacac aaaattaaac agcatattaa 11040
cacaatatcg atctagtgag gtaaaaaacc atggttttat attgatagat aatcatactc 11100
ttagtggatt ccaatttatt ttgaatcaat atggttgtat agtttatcat aaggaactca 11160
aaagaattac tgtgacaact tataatcaat tcttgacatg gaaagatatt agccttagta 11220
gattaaatgt ttgtttgatt acatggatta gtaactgttt gaacacatta aacaaaagct 11280
taggcttaag atgtggattc aataatgtta tcttgacaca attattcctt tatggagatt 11340
gtatactaaa actattccac aatgaggggt tctacataat aaaagaggta gagggattta 11400
ttatgtctct aattttaaat ataacagaag aagatcaatt cagaaaacgg ttttataata 11460
gtatgctcaa caacatcaca gatgccgcca acaaagctca aaaaaatctg ctatcaagag 11520
tatgtcatac attattagat aagacaatat cagataatat aataaatggc agatggataa 11580
ttctattgag taagttccta aaattaatta agcttgcagg tgacaataac ctcaacaatc 11640
tgagtgaatt atattttttg ttcagaatat ttggacaccc aatggtagat gaaagacaag 11700
ccatggatgc tgttaaagtt aattgcaacg agaccaaatt ttatttgtta agtagtttga 11760
gtatgttaag aggagctttt atatatagaa ttataaaagg gtttgtaaat aattacaaca 11820
gatggcctac tttaagaaat gccattgtct tacccttaag atggttaact tactataaac 11880
taaacactta tccttccttg ttggaactta cagaaagaga tttgattgtt ctatcaggac 11940
tacgtttcta tcgagagttt cggttgccta aaaaagtgga tcttgaaatg atcataaatg 12000
ataaggctat atcacctcct aaaaatttaa tatggactag tttccctaga aattatatgc 12060
cgtcacacat acaaaattat atagaacatg aaaaattaaa attctctgat agtgataaat 12120
caagaagagt attagagtat tatttaagag ataacaaatt caatgaatgt gatttacaca 12180
actgtgtagt taatcaaagt tatcttaaca acccgaatca tgtggtatca ttgacaggca 12240
aagaaagaga actcagtgta ggtagaatgt ttgcaatgca accaggaatg ttcagacaag 12300
ttcaaatatt agcagagaaa atgatagcag aaaacatatt acaatttttc cctgaaagtc 12360
ttacaagata tggtgatcta gaactacaga aaatattaga attgaaagca ggaataagta 12420
acaaatcaaa tcgttacaat gataattaca acaattacat tagtaagtgc tctatcatca 12480
cagatctcag caaattcaat caagcatttc gatatgaaac atcatgtatt tgtagtgatg 12540
tactggatga actgcatggt gtacaatctc tattttcctg gttacattta actattcctc 12600
atgtcacaat aatatgcaca tataggcatg caccccccta tataaaggat catattgtag 12660
atcttaacaa tgtagatgag caaagtggac tatatagata tcatatgggt ggtatcgaag 12720
ggtggtgtca aaaactatgg accatagaag ctatatcact attagatcta atatctctca 12780
aagggaaatt ctcaattact gctttaatta atggtgacaa tcaatcaata gatataagta 12840
aaccagtcag actcatggaa ggtcaaactc atgctcaagc agattatttg ctagcattaa 12900
atagtctcaa attactgtat aaagagtatg caggaatagg ccacaaatta aaaggaactg 12960
agacttatat atcgagagat atgcaattta tgagtaaaac gatccaacat aacggtgtat 13020
attacccagc tagtataaag aaagtcctaa gagtgggacc gtggataaac actatacttg 13080
atgacttcaa agtgagtcta gaatctatag gtagtttgac acaagaatta gaatatagag 13140
gtgaaagtct attatgcagt ttaatattta gaaatgtatg gttatataat caaattgcat 13200
tacaacttaa aaatcatgca ttatgtaaca acaaattata tttggatata ttaaaagttc 13260
taaaacactt aaaaaccttt tttaatcttg ataacattga tacagcatta acattgtata 13320
tgaatttgcc catgttattt ggtggtggtg atcccaactt gttatatcga agtttctata 13380
gaagaactcc tgatttcctc acagaggcta tagttcactc tgtgttcata cttagttatt 13440
atacaaacca tgatttaaaa gataaacttc aagatctgtc agatgataga ttgaataagt 13500
tcttaacatg cataatcacg tttgataaaa accccaatgc tgaattcgtt acattgatga 13560
gagatcctca agctttagga tctgagaggc aagctaaaat tactagcgaa atcaatagac 13620
tggcagttac cgaggttttg agcacagctc caaacaaaat attttccaaa agtgcacaac 13680
actataccac tacagagata gatcttaatg atattatgca aaatatagaa cctacatatc 13740
ctcacgggct aagagttgtt tatgagagtt taccctttta taaagcagag aaaatagtaa 13800
atcttatatc cggtacaaaa tctataacta acatactgga aaagacttct gccatagact 13860
taacagatat tgatagagcc actgagatga tgaggaaaaa cataactttg cttataagga 13920
tattaccatt agattgtaac agagataaaa gagaaatatt gagtatggaa aacctaagta 13980
ttactgaatt aagcaaatac gttagagaaa gatcttggtc tttatccaat atagttggtg 14040
ttacatcacc cagtatcatg tatacaatgg acataaaata tacaacaagc actatagcta 14100
gtggcataat catagagaaa tataatgtca acagtttaac acgtggtgag agaggaccca 14160
ctaaaccatg ggttggttca tctacacaag agaaaaagac aatgccagtt tataatagac 14220
aagttttaac caaaaaacag agagatcaaa tagatctatt agcaaaattg gattgggtgt 14280
atgcatctat agataacaag gatgaattta tggaggaact tagcatagga actcttgggt 14340
taacatatga gaaggccaaa aaattattcc cacaatattt gagtgttaac tatttgcatc 14400
gtcttacagt cagtagtaga ccatgtgaat tccctgcatc tataccagct tatagaacta 14460
caaattatca ctttgatact agccctatta atcgcatatt aacagaaaag tatggtgatg 14520
aagatattga tatagtattc caaaactgta taagctttgg ccttagctta atgtctgtag 14580
tagaacaatt tactaatgta tgtcctaaca gaattattct catacccaag cttaatgaga 14640
tacatttgat gaaacctccc atattcacag gcgatgttga tattcacaag ttaaaacaag 14700
tgatacaaaa acaacatatg tttttaccag acaaaataag tttgactcaa tatgtggaat 14760
tattcttaag taataaaaca ctcaaatctg gatctaatgt taattctaat ttaatattgg 14820
cgcataagat atctgactat tttcataata cttacatttt gagtactaat ttagctggac 14880
attggattct tattatacaa cttatgaaag attctaaggg tatttttgaa aaagattggg 14940
gagagggata tataactgat catatgttca ttaatttgaa agttttcttc aatgcttata 15000
agacatatct cttgtgtttt cataaaggtt acggcagagc aaagctggag tgtgatatga 15060
atacttcaga tctcctatgt gtattggaat taatagacag tagttattgg aagtctatgt 15120
ctaaggtgtt tttagaacaa aaagttatca aatacattct tagccaggat gcaagtttac 15180
atagagtaaa aggatgtcat agcttcaaac tatggtttct taaacgtctt aatgtagcag 15240
aattcacagt ttgcccttgg gttgttaaca tagattatca tccaacacat atgaaagcaa 15300
tattaactta tattgatctt gttagaatgg gattgataaa tatagataga atatacatta 15360
aaaataaaca caagttcaat gatgagtttt atacttctaa tctgttttac attaattata 15420
acttctcaga taatactcat ctattaacta aacatataag gattgctaat tccgaattag 15480
aaagtaatta caacaaatta tatcatccta caccagaaac cctagaaaat atactaacca 15540
atccggttaa aagtaatgag aaaaagacac tgagtgacta ttgtataggt aaaaatgttg 15600
actcaataat gttaccatcg ttatctaata agaagcttat taaatcgtct acaatgatta 15660
gaaccaatta cagcagacaa gatttgtata atttatttcc tacggttgtg attgataaaa 15720
ttatagatca ttcaggtaat acagccaaat ctaaccaact ttacactact acttctcatc 15780
aaatatcctt agtgcacaat agcacatcac tttattgcat gcttccttgg catcatatta 15840
atagattcaa ttttgtattt agttctacag gttgtaaaat tagtatagag tatattttaa 15900
aagatcttaa aattaaggat cctaattgta tagcattcat aggtgaagga gcagggaatt 15960
tattattgcg tacagtagtg gaacttcatc ctgatataag atatatttac agaagtctga 16020
aagattgcaa tgatcatagt ttaccaattg agtttttaag gctgtacaat ggacatatca 16080
acattgatta tggtgaaaat ttgaccattc ctgctacaga tgcaaccaac aacattcatt 16140
ggtcttattt acatataaag tttgctgaac ctatcagtct ttttgtctgt gatgctgaat 16200
tgcctgtaac agtcaactgg agtaagatta taatagagtg gagcaagcat gtaagaaaat 16260
gcaagtactg ttcttcagtt aataaatgta cattgatagt aaaatatcat gctcaagatg 16320
atatcgattt caaattagac aacataacta tattaaaaac ttatgtatgc ttaggtagta 16380
agttaaaggg atctgaagtt tacttagtcc ttacaatagg tcctgcaaat gtgttcccag 16440
tatttaatgt agtacaaaat gctaaattga tactatcaag aactaaaaat ttcatcatgc 16500
ctaaaaaagc tgataaagag tctattgatg caaatattaa gagtttgata ccctttcttt 16560
gttaccctat aacaaaaaaa ggaattaata ctgcattgtc taaattaaag agtgttgtta 16620
gtggagatat actatcatat tctatagctg gacgtaatga agttttcagc aataaactta 16680
taaatcataa gcatatgaac atcttaaagt ggttcaatca tgttttaaat ttcagatcaa 16740
cagaattaaa ctataatcat ttatatatgg tagaatctac ttatcctcat ctaagtgaat 16800
tgttaaacag cttgacaacc aatgaactta aaaaactgat taaaatcaca ggtagtttgt 16860
tatacaactt ttataatgaa taatgagcaa aaatcttata acaaaaatag ctacacacta 16920
acattgtatt caattatagt tattgaaaat taataattat ataattttta ataacttcta 16980
gtgaactaat cctaaaatta tcattttgat ctaggaagaa taagtttaaa tccaaatcta 17040
attggtttat atgtatatta actaaattac gagatattag tttttgacac tttttttctc 17100
gtggccggca tggtcccagc ctcctcgctg gcgccggctg ggcaacatgc ttcggcatgg 17160
cgaatgggac tagcataacc ccttggggcc tctaaacggg tcttgagggg ttttttg 17217
<210> 8
<211> 1176
<212> DNA
<213> respiratory syncytial virus
<400> 8
atggctctta gcaaagtcaa gttgaatgat acactcaaca aagatcaact tctatcatcc 60
agcaaatata ccatccaacg gagcacagga gacagcattg acactcctaa ttatgatgtg 120
cagaaacaca ttaataagtt atgtggcatg ttattaatca cagaagatgc taatcataaa 180
ttcactgggt taataggtat gttatatgct atgtctagat taggaagaga agacaccata 240
aaaatactca aagatgcggg atatcatgtt aaggcaaatg gagtggatgt aacaacacat 300
cgtcaagaca ttaatgggaa agaaatgaaa tttgaagtgt taacattagc aagcttaaca 360
actgaaattc aaatcaacat tgagatagaa tctagaaaat cctacaaaaa aatgctaaaa 420
gaaatgggag aggtggctcc agaatacagg catgactctc ctgattgtgg gatgataata 480
ttatgtatag cggcattagt aataaccaaa ttagcagcag gagatagatc aggtcttaca 540
gctgtgatta ggagagctaa taatgtccta aaaaatgaaa tgaaacgtta taaaggttta 600
ttacccaagg atatagccaa cagcttctat gaagtgtttg aaaaatatcc tcactttata 660
gatgtttttg ttcattttgg tatagcacaa tcttctacca gaggtggcag tagagttgaa 720
gggatttttg caggattgtt tatgaatgcc tatggtgcag ggcaagtgat gttacggtgg 780
ggggtcttag caaaatcagt taaaaacatt atgttaggac acgctagtgt acaagcagaa 840
atggaacaag ttgtggaggt gtatgagtat gctcagaaat tgggtggaga agcaggattc 900
taccatatat tgaacaaccc aaaagcatca ctattatctt tgactcaatt tcctcacttc 960
tctagtgtag tattgggcaa tgctgctggc ctaggcataa tgggagaata cagaggtaca 1020
ccaaggaatc aagatttata tgatgctgca aaagcatatg ctgaacaact caaagaaaat 1080
ggtgtgatta actacagtgt attagatttg acagcagaag aactagaggc tatcaaacat 1140
cagcttaatc caaaagataa tgatgtagag ctttga 1176
<210> 9
<211> 726
<212> DNA
<213> respiratory syncytial virus
<400> 9
atggaaaagt ttgctcctga attccatgga gaagatgcaa acaacagagc caccaaattc 60
ctagaatcaa taaagggcaa attcacatca cccaaagatc ccaagaaaaa agatagtatc 120
atatctgtca actcaataga tatagaagta accaaagaaa gccctataac atcaaattca 180
accattataa acccaataaa tgagacagat gatactgtag ggaacaagcc caattatcaa 240
agaaagcctc tagtaagttt caaagaagac cctacgccaa gtgataatcc tttttcaaaa 300
ctatacaaag aaaccataga aacatttgat aacaatgaag aagaatctag ctattcatat 360
gaagaaataa atgatcagac aaacgataat ataacagcaa gattagatag gattgatgag 420
aaattaagtg aaatactagg aatgcttcac acattagtag tagcgagtgc aggacccaca 480
tctgctcggg atggtataag agatgccatg gttggtttaa gagaagaaat gatagaaaaa 540
atcagaactg aagcattaat gaccaatgac agactagaag ctatggcaag actcaggaat 600
gaagaaagtg aaaagatggc aaaagacaca tcagatgaag tgtctctcaa tccaacatca 660
gagaaactga acaacctgtt ggaagggaat gatagtgaca atgatctatc acttgaagat 720
ttctga 726
<210> 10
<211> 585
<212> DNA
<213> respiratory syncytial virus
<400> 10
atgtcacgaa ggaatccttg caaattcgaa attcgaggtc attgcttgaa tggtaaaagg 60
tgtcatttta gtcataatta ttttgaatgg ccaccccatg cactgcttgt aagacaaaac 120
tttatgttaa acagaatact taagtctatg gataaaagca tagatacttt gtcagaaata 180
agtggagctg cagagttgga cagaacagaa gagtatgccc tcggtgtagt tggagtgcta 240
gagagttata taggatcaat aaataatata actaaacaat cagcatgtgt tgccatgagc 300
aaactcctta ctgaactcaa cagcgatgac atcaaaaaac taagggacaa tgaagagcca 360
aactcaccca aagtaagagt gtacaatact gtcatatcat atattgaaag caacaggaag 420
aacaataaac aaactatcca tctgttaaaa agattgccag cagacgtatt gaagaaaacc 480
atcaaaaaca cattggatat ccacaagagc ataaccatca ataacccaaa agaatcaact 540
gttagtgata cgaacgacca tgccaaaaat aatgatacta cctga 585
<210> 11
<211> 6498
<212> DNA
<213> respiratory syncytial virus
<400> 11
atggatccca ttattagtgg aaattctgct aatgtttatc taactgatag ttatttaaaa 60
ggtgttattt ctttctcaga atgtaacgct ttaggaagtt acatattcaa tggtccttat 120
ctcaaaaatg attataccaa cttaattagt agacaaaatc cattaataga acacataaat 180
ctaaagaaac taaatataac acagtcctta atatctaagt atcataaagg tgaaataaaa 240
atagaagaac ctacttactt tcagtcatta cttatgacat acaagagtat gacctcttca 300
gaacagacta ctactactaa tttacttaaa aagataataa gaagagctat agaaatcagt 360
gatgtcaaag tctatgctat attgaataaa ctggggctca aagaaaaaga caagattaaa 420
tccaataatg gacaagatga agacaactca gtcattacta ccataatcaa agatgatata 480
cttttagctg tcaaggataa tcaatctcat cttaaagcag acaaaaatca atccacaaaa 540
caaaaagata caatcaaaac aacacttttg aagaaattaa tgtgttcgat gcaacatcct 600
ccatcatggt taatacattg gtttaattta tacacaaaat taaacagcat attaacacaa 660
tatcgatcta gtgaggtaaa aaaccatggt tttatattga tagataatca tactcttagt 720
ggattccaat ttattttgaa tcaatatggt tgtatagttt atcataagga actcaaaaga 780
attactgtga caacttataa tcaattcttg acatggaaag atattagcct tagtagatta 840
aatgtttgtt tgattacatg gattagtaac tgtttgaaca cattaaacaa aagcttaggc 900
ttaagatgtg gattcaataa tgttatcttg acacaattat tcctttatgg agattgtata 960
ctaaaactat tccacaatga ggggttctac ataataaaag aggtagaggg atttattatg 1020
tctctaattt taaatataac agaagaagat caattcagaa aacggtttta taatagtatg 1080
ctcaacaaca tcacagatgc cgccaacaaa gctcaaaaaa atctgctatc aagagtatgt 1140
catacattat tagataagac aatatcagat aatataataa atggcagatg gataattcta 1200
ttgagtaagt tcctaaaatt aattaagctt gcaggtgaca ataacctcaa caatctgagt 1260
gaattatatt ttttgttcag aatatttgga cacccaatgg tagatgaaag acaagccatg 1320
gatgctgtta aagttaattg caacgagacc aaattttatt tgttaagtag tttgagtatg 1380
ttaagaggag cttttatata tagaattata aaagggtttg taaataatta caacagatgg 1440
cctactttaa gaaatgccat tgtcttaccc ttaagatggt taacttacta taaactaaac 1500
acttatcctt ccttgttgga acttacagaa agagatttga ttgttctatc aggactacgt 1560
ttctatcgag agtttcggtt gcctaaaaaa gtggatcttg aaatgatcat aaatgataag 1620
gctatatcac ctcctaaaaa tttaatatgg actagtttcc ctagaaatta tatgccgtca 1680
cacatacaaa attatataga acatgaaaaa ttaaaattct ctgatagtga taaatcaaga 1740
agagtattag agtattattt aagagataac aaattcaatg aatgtgattt acacaactgt 1800
gtagttaatc aaagttatct taacaacccg aatcatgtgg tatcattgac aggcaaagaa 1860
agagaactca gtgtaggtag aatgtttgca atgcaaccag gaatgttcag acaagttcaa 1920
atattagcag agaaaatgat agcagaaaac atattacaat ttttccctga aagtcttaca 1980
agatatggtg atctagaact acagaaaata ttagaattga aagcaggaat aagtaacaaa 2040
tcaaatcgtt acaatgataa ttacaacaat tacattagta agtgctctat catcacagat 2100
ctcagcaaat tcaatcaagc atttcgatat gaaacatcat gtatttgtag tgatgtactg 2160
gatgaactgc atggtgtaca atctctattt tcctggttac atttaactat tcctcatgtc 2220
acaataatat gcacatatag gcatgcaccc ccctatataa aggatcatat tgtagatctt 2280
aacaatgtag atgagcaaag tggactatat agatatcata tgggtggtat cgaagggtgg 2340
tgtcaaaaac tatggaccat agaagctata tcactattag atctaatatc tctcaaaggg 2400
aaattctcaa ttactgcttt aattaatggt gacaatcaat caatagatat aagtaaacca 2460
gtcagactca tggaaggtca aactcatgct caagcagatt atttgctagc attaaatagt 2520
ctcaaattac tgtataaaga gtatgcagga ataggccaca aattaaaagg aactgagact 2580
tatatatcga gagatatgca atttatgagt aaaacgatcc aacataacgg tgtatattac 2640
ccagctagta taaagaaagt cctaagagtg ggaccgtgga taaacactat acttgatgac 2700
ttcaaagtga gtctagaatc tataggtagt ttgacacaag aattagaata tagaggtgaa 2760
agtctattat gcagtttaat atttagaaat gtatggttat ataatcaaat tgcattacaa 2820
cttaaaaatc atgcattatg taacaacaaa ttatatttgg atatattaaa agttctaaaa 2880
cacttaaaaa ccttttttaa tcttgataac attgatacag cattaacatt gtatatgaat 2940
ttgcccatgt tatttggtgg tggtgatccc aacttgttat atcgaagttt ctatagaaga 3000
actcctgatt tcctcacaga ggctatagtt cactctgtgt tcatacttag ttattataca 3060
aaccatgatt taaaagataa acttcaagat ctgtcagatg atagattgaa taagttctta 3120
acatgcataa tcacgtttga taaaaacccc aatgctgaat tcgttacatt gatgagagat 3180
cctcaagctt taggatctga gaggcaagct aaaattacta gcgaaatcaa tagactggca 3240
gttaccgagg ttttgagcac agctccaaac aaaatatttt ccaaaagtgc acaacactat 3300
accactacag agatagatct taatgatatt atgcaaaata tagaacctac atatcctcac 3360
gggctaagag ttgtttatga gagtttaccc ttttataaag cagagaaaat agtaaatctt 3420
atatccggta caaaatctat aactaacata ctggaaaaga cttctgccat agacttaaca 3480
gatattgata gagccactga gatgatgagg aaaaacataa ctttgcttat aaggatatta 3540
ccattagatt gtaacagaga taaaagagaa atattgagta tggaaaacct aagtattact 3600
gaattaagca aatacgttag agaaagatct tggtctttat ccaatatagt tggtgttaca 3660
tcacccagta tcatgtatac aatggacata aaatatacaa caagcactat agctagtggc 3720
ataatcatag agaaatataa tgtcaacagt ttaacacgtg gtgagagagg acccactaaa 3780
ccatgggttg gttcatctac acaagagaaa aagacaatgc cagtttataa tagacaagtt 3840
ttaaccaaaa aacagagaga tcaaatagat ctattagcaa aattggattg ggtgtatgca 3900
tctatagata acaaggatga atttatggag gaacttagca taggaactct tgggttaaca 3960
tatgagaagg ccaaaaaatt attcccacaa tatttgagtg ttaactattt gcatcgtctt 4020
acagtcagta gtagaccatg tgaattccct gcatctatac cagcttatag aactacaaat 4080
tatcactttg atactagccc tattaatcgc atattaacag aaaagtatgg tgatgaagat 4140
attgatatag tattccaaaa ctgtataagc tttggcctta gcttaatgtc tgtagtagaa 4200
caatttacta atgtatgtcc taacagaatt attctcatac ccaagcttaa tgagatacat 4260
ttgatgaaac ctcccatatt cacaggcgat gttgatattc acaagttaaa acaagtgata 4320
caaaaacaac atatgttttt accagacaaa ataagtttga ctcaatatgt ggaattattc 4380
ttaagtaata aaacactcaa atctggatct aatgttaatt ctaatttaat attggcgcat 4440
aagatatctg actattttca taatacttac attttgagta ctaatttagc tggacattgg 4500
attcttatta tacaacttat gaaagattct aagggtattt ttgaaaaaga ttggggagag 4560
ggatatataa ctgatcatat gttcattaat ttgaaagttt tcttcaatgc ttataagaca 4620
tatctcttgt gttttcataa aggttacggc agagcaaagc tggagtgtga tatgaatact 4680
tcagatctcc tatgtgtatt ggaattaata gacagtagtt attggaagtc tatgtctaag 4740
gtgtttttag aacaaaaagt tatcaaatac attcttagcc aggatgcaag tttacataga 4800
gtaaaaggat gtcatagctt caaactatgg tttcttaaac gtcttaatgt agcagaattc 4860
acagtttgcc cttgggttgt taacatagat tatcatccaa cacatatgaa agcaatatta 4920
acttatattg atcttgttag aatgggattg ataaatatag atagaatata cattaaaaat 4980
aaacacaagt tcaatgatga gttttatact tctaatctgt tttacattaa ttataacttc 5040
tcagataata ctcatctatt aactaaacat ataaggattg ctaattccga attagaaagt 5100
aattacaaca aattatatca tcctacacca gaaaccctag aaaatatact aaccaatccg 5160
gttaaaagta atgagaaaaa gacactgagt gactattgta taggtaaaaa tgttgactca 5220
ataatgttac catcgttatc taataagaag cttattaaat cgtctacaat gattagaacc 5280
aattacagca gacaagattt gtataattta tttcctacgg ttgtgattga taaaattata 5340
gatcattcag gtaatacagc caaatctaac caactttaca ctactacttc tcatcaaata 5400
tccttagtgc acaatagcac atcactttat tgcatgcttc cttggcatca tattaataga 5460
ttcaattttg tatttagttc tacaggttgt aaaattagta tagagtatat tttaaaagat 5520
cttaaaatta aggatcctaa ttgtatagca ttcataggtg aaggagcagg gaatttatta 5580
ttgcgtacag tagtggaact tcatcctgat ataagatata tttacagaag tctgaaagat 5640
tgcaatgatc atagtttacc aattgagttt ttaaggctgt acaatggaca tatcaacatt 5700
gattatggtg aaaatttgac cattcctgct acagatgcaa ccaacaacat tcattggtct 5760
tatttacata taaagtttgc tgaacctatc agtctttttg tctgtgatgc tgaattgcct 5820
gtaacagtca actggagtaa gattataata gagtggagca agcatgtaag aaaatgcaag 5880
tactgttctt cagttaataa atgtacattg atagtaaaat atcatgctca agatgatatc 5940
gatttcaaat tagacaacat aactatatta aaaacttatg tatgcttagg tagtaagtta 6000
aagggatctg aagtttactt agtccttaca ataggtcctg caaatgtgtt cccagtattt 6060
aatgtagtac aaaatgctaa attgatacta tcaagaacta aaaatttcat catgcctaaa 6120
aaagctgata aagagtctat tgatgcaaat attaagagtt tgataccctt tctttgttac 6180
cctataacaa aaaaaggaat taatactgca ttgtctaaat taaagagtgt tgttagtgga 6240
gatatactat catattctat agctggacgt aatgaagttt tcagcaataa acttataaat 6300
cataagcata tgaacatctt aaagtggttc aatcatgttt taaatttcag atcaacagaa 6360
ttaaactata atcatttata tatggtagaa tctacttatc ctcatctaag tgaattgtta 6420
aacagcttga caaccaatga acttaaaaaa ctgattaaaa tcacaggtag tttgttatac 6480
aacttttata atgaataa 6498
Claims (15)
- RSV의 외피 단백질을 코딩하는 유전자가 재배열된 유전자 재조합 호흡기 세포융합 바이러스(RSV)로,
RSV의 당단백질(G 단백질)과 융합 단백질 (F 단백질)을 코딩하는 유전자 사이에 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자가 삽입되거나,
RSV의 F 단백질을 코딩하는 유전자가 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자로 치환된 유전자 재조합 호흡기 세포융합 바이러스. - 제1항에 있어서, 상기 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스는 Aquaparamyxovirus, Avulavirus, Ferlavirus, Henipavirus, Morbillivirus, Respirovirus , Rubulavirus, Metapneumovirus, 및 Orthopneumovirus로 이루어진 군에서 선택된 어느 하나 이상인 것을 특징으로 하는 유전자 재조합 호흡기 세포융합 바이러스(RSV).
- 제1항에 있어서, 상기 이종 바이러스는 홍역 바이러스(Measles virus), 및 뉴캐슬병 바이러스(Newcastle disease virus)로 이루어진 군에서 선택된 어느 하나 이상인, 유전자 재조합 호흡기 세포융합 바이러스(RSV).
- 제1항에 있어서, 상기 유전자 재조합 호흡기 세포융합 바이러스(RSV)는 서열번호 1의 야생형 인간 RSV A 바이러스주의 외피 단백질을 코딩하는 유전자가 재배열된, 재조합 RSV.
- 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드를 포함하는 제1 발현 벡터; 및
N, P, L, 및 M2-1 단백질로 이루어진 군에서 선택된 어느 하나 이상의 단백질을 코딩하는 폴리뉴클레오티드를 포함하는 제2 발현 벡터를 함께 발현시켜 재조합 RSV를 생산하며,
상기 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드는 이종의 바이러스로부터 유래된 단백질의 전체 또는 일부 도메인을 암호화하는 폴리뉴클레오티드가 포함된, 약독화된 재조합 RSV를 제조하는 방법. - 제5항에 있어서, 상기 제1 발현 벡터에 포함되는 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드는 서열번호 4 내지 7 중에서 선택된 어느 하나인, 방법.
- 제6항에 있어서, 상기 서열번호 4 내지 7 중에서 선택된 어느 하나의 폴리뉴클레오티드는 cDNA인, 방법.
- 제5항에 있어서, 상기 제1 발현 벡터는 pCC1 플라스미드에 상기 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드가 포함된, 방법.
- 제5항에 있어서, 상기 재조합 RSV 안티게놈을 코딩하는 폴리뉴클레오티드는 이종의 바이러스로부터 유래된 단백질은 F 단백질인 것을 특징으로 하는, 방법.
- 재조합 RSV 발현벡터로,
RSV의 당단백질(G 단백질)과 융합 단백질 (F 단백질)을 코딩하는 유전자를 포함하되, 상기 G 단백질과 F 단백질을 코딩하는 유전자 사이에 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자가 삽입되거나,
RSV의 융합 단백질 (F 단백질)을 코딩하는 유전자 대신 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스 유래의 F 단백질을 코딩하는 유전자로 치환된 재조합 RSV 유전자가 포함된, 재조합 RSV 발현용 벡터. - 제10항에 있어서, 상기 재조합 RSV 유전자는 서열번호 4 내지 7 중에서 선택된 어느 하나인 재조합 RSV 발현용 벡터.
- 제10항에 있어서, 상기 재조합 RSV 발현용 벡터는 T7 프로모터, 해머헤드 라이보좀, 재조합 RSV 유전자, 헤파티티스 델타 바이러스 라이보좀; 및 T7 종결자를 순서대로 포함하는 것을 특징으로 하는 재조합 RSV 발현용 벡터.
- 제10항에 있어서, 상기 Paramyxoviridae, 또는 Pneumoviridae 바이러스과의 이종 바이러스는 홍역 바이러스(Measles virus), 및 뉴캐슬병 바이러스(Newcastle disease virus)로 이루어진 군에서 선택된 어느 하나 이상인 재조합 RSV 발현용 벡터.
- 제1항 내지 제4항 중 어느 하나의 항에 따른 유전자 재조합 호흡기 세포융합 바이러스(RSV) 및
약학적으로 허용 가능한 담체를 포함하는 약독화된 RSV 생백신 조성물. - 제1항 내지 제4항 중 어느 하나의 항에 따른 유전자 재조합 호흡기 세포융합 바이러스(RSV) 및
약학적으로 허용 가능한 담체를 포함하는, RSV; 및 홍역 바이러스(Measles virus (MV)) 또는 뉴캐슬병 바이러스(Newcastle disease virus(NDV)) 감염 예방용 2가 백신 조성물.
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