JP2016121172A - 哺乳動物及びヒトの細胞においてhiv複製を阻害する方法 - Google Patents
哺乳動物及びヒトの細胞においてhiv複製を阻害する方法 Download PDFInfo
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Abstract
Description
本発明は、ウイルス耐性を回避する又はその出現確率を最低限に抑えるので、現在入手可能な抗レトロウイルス薬よりも有利である。本発明は、ウイルス起源ではなく細胞の内因性IF、特にビメンチン及びケラチン−10タンパク質に基づく。
製剤化されると、本発明の医薬組成物は、(1)対象に直接投与される、(2)対象に由来する細胞にex vivoで送達される、又は(3)組換えタンパク質発現用としてin vitroで送達されることができる。
抗HIV活性を示す白血球抽出物で処理されたMT4細胞の比較プロテオミクス
MT4細胞系を、抗HIV活性を示す白血球抽出物で処理し(Fernandez−Ortega C;Dubed M;Ruibal I;Vilarrubia OL;Menendez JC;NaveaLら、1996、Biotherapy 9:33〜40)、得られたタンパク質発現プロファイルを、未処理細胞の対照と比較した。細胞を溶解し、12000rpmで20分間遠心分離した。上清を集め、ペレットについて2回目の溶解手順を実施した。同一条件下で2回目の遠心分離ステップを行った後、2回目の上清を1回目のものと一緒に集め、更にエチルアルコールで脱脂処理し、そしてポリアクリルアミドでアルキル化した。その後、デオキシリボ核酸(DNA)を沈殿させ、このサンプルについて、12.5から3%のトリス−トリシンポリアクリルアミドゲルを用いて、4℃で二次元電気泳動を実施した。
ビメンチン及びケラチン−10に対する干渉RNAは、HIV感染を阻害する。
ビメンチン及びケラチンタンパク質の発現をそれぞれ発現抑制するRNAヘアピンをコードする配列を保持するpLenti−shRNAvim又はpLenti−shRNAK−10レンチウイルスベクターを用いてMT4細胞系に形質導入を行った。これらのレンチウイルスベクターを、4つのプラスミドを用いて形質導入された293T細胞系内でパッケージングすることにより会合させた。前記プラスミドはpLP1、pLP2、pLP/VSVG、及びp−shRNAであり、この最後のものはビメンチン又はケラチン−10のいずれかに特異的であった。pLP1ベクターは、HIV−1のgag/pol配列に関する遺伝子産物をコードする。pLP/VSVGは、水疱性口内炎ウイルスの表面タンパク質をコードし、またp−shRNAは、ビメンチン−又はケラチン−10−特異的RNAヘアピンをコードする配列を保持するレンチウイルスベクターのゲノムを含有する(Ui−Tei K,Naito Y,Takahashi F,Haraguchi Tら,2004 Nucleic Acids Research 32:936〜948;Santa Cruz Biotechnology)。すべてのプラスミドは、アンピシリン選択下、大腸菌(Escherichia coli)XL−1系統内で増幅した。4つのプラスミドベクターを、カラムクロマトグラフィーによりトランスフェクション品質に精製し、一緒にしてポリエチレンイミン存在下、293Tパッケージング細胞系と接触させた。細胞を37℃、5%CO2雰囲気下で48時間インキュベーションし、ビリオンを超遠心分離により20000×gで更に精製した。レンチウイルスベクターを精製したら、MT4細胞に形質導入を行い、組換え体をブラストサイジン耐性について選別した。組換えクローンを限界希釈法により単離し、採集するまでこれを5%CO2雰囲気下、95%相対湿度、37℃で、ウシ胎仔血清(FBS)が10%となるように補給されたRPMI培地内で培養した。総タンパク質を培養物から抽出し、またビメンチンの発現抑制をMT4(MT4vim(S))細胞内で、並びにケラチン−10については、ケラチン−10が発現抑制されたMT4K−10(S)細胞内でウェスタンブロットを行うことにより実証した。形質導入された培養物では、MT4の形質導入されない対照と比較してビメンチン又はケラチン−10の発現がそれぞれ低下していることが明らかとなった(図2)。
系A:ビメンチンタンパク質について安定的に発現抑制された細胞(MT4vim(S))又はケラチン−10について安定的に発現抑制された細胞(MT4K−10(S))を、5%CO2雰囲気下、95%相対湿度、37℃で、FBSが10%となるように補給されたRPMI培地内で培養した。総ウイルスによるチャレンジ試験を、MT4vim(S)、MT4K−10(S)、及びMT4細胞培養物について実施した。Bruウイルス系統を0.01のm.o.i.で用い、ELISA法により培養物上清内のp24抗原濃度を測定することから複製を評価した。これらのタンパク質それぞれについて発現抑制されていないMT4細胞培養物と比較して、MT4vim(S)及びMT4K−10(S)細胞は、ウイルス複製について約90%の阻害を示した(図3)。
MT4細胞内中間フィラメントの構造変化
最初に、MT4vim(S)、MT4K−10(S)、及びMT4細胞を、3.2%グルタルアルデヒド内で4℃にて1時間固定し、次に2%四酸化オスミウム内で4℃、1時間固定した。これらをその後0.1Mリン酸緩衝化生理食塩水(PBS)、pH7.2で洗浄し、エタノール濃度を増加させながら(30、50、70、及び100%)、4℃で各10分間脱水した。封入を行い、極薄い40〜50nm幅の切片を、ウルトラミクロトーム(NOVA、LKB)で採取し、これを400孔のニッケルトレイ上に配置した。極薄い切片を採取しトレイ上に配置したら、これらを飽和酢酸ウラニウム及びクエン酸鉛で造影し、JEOL JEM 2000EX(JEOL)顕微鏡下で更に調べた。顕微鏡写真5例を異なる倍率で分析した。MT4細胞の未処理状態のIFを図5Aに示すが、一方これらの構造物は、MT4vim(S)、MT4K−10(S)細胞では短縮した状態で現れた(それぞれ図5B及びC)。セクションDは、MT4細胞内のビメンチン構造を分解するペプチド(配列番号1として識別されるペプチド)の作用により引き起こされたIF内の効果を示す。ウイルス複製阻害を、上記条件下で観察した。ビメンチン又はケラチン−10タンパク質が、免疫顕微鏡によりIFにおいて識別された。
MT4細胞内でHIV複製を阻害する合成ペプチド
ヒトケラチン−10、ヒトケラチン1、及びヒトビメンチンのアミノ酸配列に対応するペプチドを合成した(Goldman RD,Khuon S,Hao Chou Y,Opal P,Steinert PM 1996,J Cell Biol 134:971〜983;Steinert PM,Yang JM,Bale SJ,Compton JG 1993,BBRC 197:840〜848)。これらのペプチドのうちの1つは、そのC末端に結合した細胞貫通ペプチドを有する(Vallespi MG,Fernandez JR,Torrens I,Garcia I,Garay H,Mendoza Oら、2009.J Peptide Science 16:40〜47)。前記ペプチドの抗HIV活性を、異なるウイルス系統:HXB1(HIV−1 IIIBクローン)及びBruの存在下で総ウイルスチャレンジ系を用いて評価した。ウイルスチャレンジ前に、MT4細胞系をペプチドと共に24時間インキュベーションした。各実験用変異体について9個の複製物を含め、0.01及び0.05のm.o.i.値で分析を行った。p24ウイルス抗原の値を、細胞培養物内でELISAタイプ分析法を用いて求め、結果を、いずれについてもペプチド濃度に対してウイルス阻害の割合(%)又は感染の割合(%)として表した。培養物を高ウイルス濃度(配列番号1、図6A)及び0.01のm.o.i.(図6B)でチャレンジ試験したときに、いずれについてもペプチドの存在下でウイルス複製の重要な阻害が認められた。ペプチドのIC50は、ナノモル範囲であった。
末梢血単核球においてHIV複製を阻害する合成ペプチド
PBMCを健常個体の全血から塩化セシウムFicoll密度勾配法により単離した。20%のFBS、100U/mLのインターロイキン2(IL−2)、及び5μg/mLのフィトヘマグルチニン(PHA)となるように補給されたRPMI培地内において2日間細胞を事前刺激した。その後、上記細胞を、PHAを含まない培地内で保持し、96ウェルプレートのウェル1個当り150000個の細胞を播種した。24時間後、異なる濃度でペプチドを添加し、培養物を、0.01のm.o.i.でHIV−1 Bru系統に感染させた。3日置きに培地を交換し、ペプチドを添加しながら、培養物を7日間保持した。培養物を採集し、上清を集めてp24ウイルスタンパク質の有無を評価した。ペプチドは用量依存的にHIV−1複製を阻害した(図7)。HIV−1 BaL1系統に感染した培養物では、ナノモル範囲の類似したIC50結果が得られた。
合成ペプチドによるHIV−2の阻害
PBMCを、Ficoll密度勾配法を用いて健常個体の全血から単離した。20%のFBS、100U/mLのIL−2、及び5μg/mLのPHAとなるように補給されたRPMI培地を用いて、細胞を2日間事前刺激した。その後細胞を、PHAを含まない培地内で維持し、96ウェルプレートのウェル1個当り150000個の細胞を播種した。24時間後、異なる濃度でペプチドを添加し、培養物を、CBL−20 HIV−2系統に感染させた。3日置きに培地を交換し、ペプチドを添加しながら、培養物を7日間保持した。培養物を採集し、上清を集めてp24ウイルスタンパク質の有無を評価した。ペプチドは用量依存的にHIV−2複製を阻害した(図8)。
配列番号1、4、5、7、8、及び9として識別されるペプチド存在下におけるビメンチンの低下
MT4細胞系を、各ペプチドにつき50μMで24時間インキュベーションした。ビメンチンタンパク質をウェスタンブロット技術により検出した。細胞抽出物を1%ドデシル硫酸ナトリウム(SDS)に再懸濁し、10%ポリアクリルアミドゲルに適用し、更にHybond−Pセルロース膜に移行させた。免疫学的同定を目的として、抗ビメンチン及び抗βアクチン(対照として)抗体を用いた。二次抗体として抗マウスIgG抗体−ペルオキシダーゼコンジュゲートを用いた。過酸化水素及びPBSの存在下でジアミノベンジジンを用いて、ペルオキシダーゼ酵素の活性を可視化した。ペプチドで処理したMT4細胞ではビメンチンタンパク質が低下した(図9)。
配列番号1及び配列番号3として識別されるペプチドの細胞貫通
HeLa CD4+細胞を、10%FBSとなるように補給したRPMI培地に播種し、単層の60%コンフルエンスに達するまでインキュベーションした。MT4細胞を、1ウェル当り50000個の細胞となるように10%FBSのRPMI培地内に播種した。配列番号1及び配列番号3として識別されるペプチドを注射液に再懸濁し、5、10、20、及び40μMの濃度で評価した。ペプチドを、5%CO2雰囲気下、37℃で24時間インキュベーションし、貫通を、15、30、及び60分後に評価した。各時間経過後、細胞を採集し、フローサイトメトリーにより速やかに分析した。1つの実験用変異体につき3つの複製物を分析した。図10に示す通り、ペプチドは、MT4細胞内に独自に貫通可能であった。
ビメンチンと結合し、HIV−1複製を阻害する脂質誘導体
プロスタグランジンシクロペンタン15デオキシ−Δ−12,14−PGJ2(15d−PGJ2)はビメンチンタンパク質と結合することが公知である(Stamatakis K,Sanchez−Gomez FJ,Perez−Sala D 2006,J Am Soc Nephrol 17:89〜98)。本発明では、15d−PGJ2はin vitroでHIV複製を阻害することが実証された。抗ウイルス活性分析を、HIV−1(Bru系統)チャレンジの対象とされたMT4細胞について実施した。細胞を異なる濃度の15d−PGJ2でインキュベーションし、更に0.01のm.o.i.でHIV−1チャレンジの対象とした。5日間インキュベーションした後、細胞培養物を採集し、上清中のp24タンパク質を評価した(図11)。
合成ペプチド及び15d−PGJ2がHIV−1に感染した患者のPBMCに与える効果
PBMCを、Ficoll密度勾配法によりHIV−1感染個体の全血から単離した。細胞を事前刺激し、例5に記載するのと同様にペプチドで処理し、又は5μMの15d−PGJ2で処理した。培養物上清についてELISA法によりp24抗原濃度を測定することから、複製物を評価した。ペプチド又は脂質誘導体で処理したPBMCでは、未処理細胞と比較してp24の値は有意に低下した(表1)。これは、上記化合物を用いた処理によりもたらされたHIV−1複製の阻害を示唆する。
例3に記載する試験法に従い、IF構造を伝達電子顕微鏡検査により分析した。IFは、ペプチド又は脂質誘導体で治療を受けた感染個体のPBMCでは、未処理細胞と比較して非常に短いことが明らかとなった。
ビメンチン及びケラチン−10を標的とする干渉RNAは、感染個体のPBMCに存在するHIVを阻害する。
Ficoll密度勾配法により、PBMCをHIV−1感染個体の全血から単離した。20%FBS、100U/mLのIL−2、及び5μg/mLのPHAとしたRPMI培地内で細胞を2日間事前刺激した。その後、上記細胞を、PHAを含まない培地内で保持し、更にビメンチン及びケラチン−10タンパク質のそれぞれを発現抑制させるRNAヘアピンをコードする配列を保持するレンチウイルスベクターpLenti−shRNAvim、又はpLenti−shRNAK−10を用いて形質導入した。例2に記載するようにベクターを得た。ELISA法で培養物上清のp24抗原濃度を測定することにより、複製物を評価した。ビメンチン又はケラチン−10タンパク質について発現抑制されたPBMCは、上記タンパク質のそれぞれについて発現抑制されていない培養物と比較して、高いウイルス複製阻害を示した(表2)。
例3に記載する試験法に従い、IF構造を伝達電子顕微鏡検査により分析した。IF構造は、レンチウイルスベクターを用いて形質導入された感染個体由来のPBMCでは、形質導入されない細胞と比較して短いことが明らかとなった。
配列番号1及び2として識別されるペプチドを含む製剤によるHIV−1感染患者の治療
診断から1年未満で、CD4+T細胞の数値が細胞350個/mm3よりも高いHIV−1血清陽性患者8例を、配列番号1として識別されるペプチドを含む製剤、又は配列番号2として識別されるペプチドを含む製剤で治療した。ペプチドを1日当り150mg投与し、ウイルス負荷及びCD4+T細胞カウントに注目して患者を6カ月間フォローアップした。治療後患者2例でウイルス負荷が検出不能となり、他の患者6例では、1.5log単位を超えて減少した。一方、患者7例は、細胞50個/mm3より多いCD4+T細胞の増加を示したが、もう一人の患者ではCD4+T細胞カウントは低下した。配列番号1として識別されるペプチドで治療を受けた患者2例、及び配列番号2で治療を受けた患者3例について、例3に記載する試験法に従い、IF構造を伝達電子顕微鏡検査により分析した。いずれの場合もIFは短縮しているように見えた。
Claims (31)
- 哺乳動物細胞において細胞骨格の中間フィラメント(IF)の構造を破壊するステップを含む、ヒト免疫不全ウイルス(HIV)の複製を阻害する方法。
- 前記IFは、ビメンチン及び/又はケラチンタンパク質を含む、請求項1に記載の方法。
- 前記IFは、ビメンチン及び/又はケラチン−10タンパク質を含む、請求項2に記載の方法。
- 前記IF中のビメンチン及び/又はケラチン−10の量を低減するステップを含む、請求項1から3までのいずれか一項に記載の方法。
- ビメンチン及び/又はケラチン−10をコードする遺伝子の発現を低減するステップを含む、請求項1から4までのいずれか一項に記載の方法。
- 前記IFの破壊は、ポリペプチド、ペプチド、核酸、及び化合物からなる群から選択される薬剤により実現される、請求項1から5までのいずれか一項に記載の方法。
- 前記薬剤は、配列番号1から配列番号10として識別されるペプチド及びその相同体の群から選択されるペプチドである、請求項6に記載の方法。
- 前記薬剤は、ビメンチン及び/又はケラチン−10遺伝子又はその転写物を標的とする干渉RNA又はアンチセンスオリゴヌクレオチドである、請求項6に記載の方法。
- 前記薬剤は、化合物又は脂質誘導体である、請求項6に記載の方法。
- HIV感染を予防又は治療する医薬の製造における、細胞骨格のIFを破壊する薬剤の使用。
- 前記IFは、ビメンチン及び/又はケラチンを含む、請求項10に記載の使用。
- 前記IFは、ビメンチン及び/又はケラチン−10を含む、請求項11に記載の使用。
- 前記薬剤は、前記IF中のビメンチン及び/又はケラチン−10の量の低減を誘発する、請求項10から12までのいずれか一項に記載の使用。
- 前記薬剤は、ビメンチン及び/又はケラチン−10をコードする遺伝子の発現の低減を実現する、請求項10から13までのいずれか一項に記載の使用。
- 前記薬剤は、ポリペプチド、ペプチド、核酸、及び化合物からなる群から選択される、請求項10から14までのいずれか一項に記載の使用。
- 前記薬剤は、配列番号1から配列番号10として識別されるペプチド又はその相同体の群から選択されるペプチドを含む、請求項15に記載の使用。
- 前記薬剤は、ビメンチン及び/又はケラチン−10遺伝子又はその転写物を標的とする干渉RNA又はアンチセンスオリゴヌクレオチドである、請求項15に記載の使用。
- 前記薬剤は、siRNA、shRNA、及びmiRNAからなる群から選択される干渉RNAである、請求項17に記載の使用。
- 前記干渉RNAは、ビメンチン及び/又はケラチン−10タンパク質のメッセンジャーRNAの領域に対して相補的な15から50個のヌクレオチド、好ましくは18から25個のヌクレオチドの配列を含む、請求項18に記載の使用。
- 前記化合物は、脂質化合物又は脂質誘導体である、請求項15に記載の使用。
- 前記脂質化合物は、プロスタグランジンシクロペンタン15デオキシ−Δ−12,14−PGJ2である、請求項20に記載の使用。
- 細胞骨格のIFを破壊する薬剤及び薬学的に許容される担体又は添加剤を含む、HIV感染を予防又は治療する医薬組成物。
- 前記薬剤は、IFを破壊するポリペプチド、ペプチド、核酸、及び化合物からなる群から選択される、請求項22に記載の組成物。
- 前記薬剤は、配列番号1から配列番号10として識別されるペプチド及びその相同体の群から選択されるペプチドを含む、請求項23に記載の組成物。
- 前記薬剤は、ビメンチン及び/又はケラチン−10遺伝子を標的とする干渉RNA又はアンチセンスオリゴヌクレオチドである、請求項23に記載の組成物。
- 前記干渉RNAは、siRNA、shRNA、又はmiRNAからなる群から選択される、請求項25に記載の組成物。
- 前記化合物は、脂質化合物又は脂質誘導体である、請求項23に記載の組成物。
- 前記脂質化合物は、プロスタグランジンシクロペンタン15デオキシ−Δ−12,14−PGJ2である、請求項27に記載の組成物。
- 細胞骨格のIFを破壊する薬剤及び抗HIV薬物を含む医薬組合せ。
- 前記薬剤及び薬物は、同一の治療スケジュールの一環として同時に、個別に、又は連続して投与される、請求項29に記載の医薬組合せ。
- それを必要とする対象においてHIV感染を治療又は予防する方法であって、前記対象に、請求項22から28までのいずれか一項に記載の医薬組成物又は請求項29から30までのいずれか一項に記載の医薬組合せの治療上有効な用量を投与するステップを含む上記方法。
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