CA2325345C - Medicaments for inducing cytotoxic t-cells - Google Patents

Medicaments for inducing cytotoxic t-cells Download PDF

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CA2325345C
CA2325345C CA2325345A CA2325345A CA2325345C CA 2325345 C CA2325345 C CA 2325345C CA 2325345 A CA2325345 A CA 2325345A CA 2325345 A CA2325345 A CA 2325345A CA 2325345 C CA2325345 C CA 2325345C
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amino acid
peptide
compound according
hiv
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CA2325345A1 (en
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Thomas Harrer
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1241—Nucleotidyltransferases (2.7.7)
    • C12N9/1276—RNA-directed DNA polymerase (2.7.7.49), i.e. reverse transcriptase or telomerase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
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  • AIDS & HIV (AREA)
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  • Tropical Medicine & Parasitology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

The invention relates to compounds containing an amino acid with the sequence X1-Y-X2-D-D-X3 or a nucleic acid coding this amino acid, X1 being at least one chosen amino acid, Y being tyrosine, X2 being an amino acid chosen from the following group: valine, isoleucine and leucine; D being aspartate and X3 being at least one other chosen amino acid, the following amino acids being excluded: TLVLQYVDDLLL and ILVLQYVDDLLL, T being threonine, V being valine, I being isoleucine, L being leucine and Q being glutamine. The invention also relates to medicaments for inducing cytotoxic T-cells, containing this class of compounds.

Description

Medicaments for Inducing C~totoxic T cells The invention relates to a compound or medicament for inducing cytotoxic T cells. The invention further relates to a vaccine against retroviruses such as HIV-1, HIV-2, HTLV-I, HTLV-II as well as against viruses such as hepatitis-B.
It is known from the prior art that by treatment with certain medicaments cytotoxic T cells (CTL) may be induced.
Cytotoxic T cells eliminate inter alia virus infected cells specifically.
In the treatment of HIV infections, inhibitors of viral enzyme reverse transcriptase are employed. One important reverse transcriptase inhibitor used clinically is the medicament 3TC (which is (-)2'-deoxy-3'-thiacytidine or lamivudine). However, HIV may become resistant to this medicament by mutating methionine to isoleucine or valine at codon 194 of reverse transcriptase (PNAS 1993: 90: 5653-6).
The same mutation also leads to resistance to other reverse transcriptase inhibitors such as 1592U89 (abacavir), zalcitabin (DDC), didanosin (DDI), and 2'deoxy-5-fluoro-3'thiacytidine (FTC). Other viruses also have reverse transcriptase or similar DNA polymerases that like HIV
reverse transcriptase contain the sequence YMDD at the active catalytic center. The same mutation of methionine to valine in the YMDD sequence of hepatitis B DNA polymerase also induces resistance in the hepatitis B virus to 3TC, a medicament used to fight the hepatitis B virus.
From the later published application WO 98/23755, the following amino acid sequences are known for the treatment of multiple sclerosis:
TLVLQYVDDLLL and ILVLQYVDDLLL, whereby T = threonine, V =
valine, I - isoleucine, L = leucine, and Q = glutamine.
The object of the invention is to make available a medicament that may be used to effectively block or positively affect the course of viral infections, particularly HIV or hepatitis B infections. This medicament should be suitable both for prevention of an infection, e.g. as a preventive vaccine, and for the therapy of an already established infection.
This object is fulfilled by the features of claim 1. Useful embodiments of the invention result from the features of claims 2 through 29.
According to the invention, a compound or medicament is provided for the induction of cytotoxic T cells containing or consisting of an amino acid or the nucleic acid encoding this amino acid, where such amino acid has the following sequence:
X1-Y-X2-D-D-X3, wherein X1 - at least one of any amino acid, Y - tyrosine, X2 - one amino acid selected from the following group: valine, isoleucine, and leucine, D - aspartate, and X3 - at least one additional of any amino acid, with the exception of the following amino acid sequences:
LRVEYLDDR, TLVLQYVDDLLL, and ILVLQYVDDLLL, with T = threonine, V = valine, I - isoleucine, L = leucine, Q = glutamine, and R = arginine;
as well as a method for prevention or treatment of infections with viruses, preferably mutated HIV, HIV-1, HIV-2, HTLV-I, or HTLV-II viruses, or mutated hepatitis-B viruses, or a disease that responds to induction of cytotoxic T cells consisting of administering effective doses of the medicament comprising the amino acid with the following sequence:
X1-Y-X2-D-D-X3, wherein X1 = at least one of any amino acid, Y - tyrosine, X2 - one amino acid selected from the following group: valine (V), isoleucine (I), and leucine (L), - aspartate, and X3 - at least one additional of any amino acid, or nucleic acid encoding such amino acid, and/or the use for producing a medicament comprising the following amino acid:
X1-Y-X2-D-D-X3, wherein X1 - at least one of any amino acid, Y - tyrosine, X2 - one amino acid selected from the following group: valine, isoleucine, and leucine, D - aspartate, and X3 - at least one additional of any amino acid, or a nucleic acid encoding such amino acid sequence for production of a medicament for the prevention or treatment of a viral infection, preferably mutated HIV, HIV-l, HIV-2, HTLV-I, HTLV-II, or mutated hepatitis B infection, or a disease which responds to induction of cytotoxic T cells.
The medicament in this invention induces cytotoxic T cells which destroy cells particularly infected with mutated HIV
viruses. Surprisingly, the sequences of this invention form T cell epitopes that are able to bind to HLA-A2 molecules and induce specific T cell receptors against themselves. Thus, it is possible to specifically target HIV mutants that arise in treatment with 3TC and abacavir.
According to one embodiment, the peptide consists of nine amino acids. X1 may consist of a sequence of four or five of any additional amino acids, X3 of one or two additional of any amino acids. Such an amino acid sequence is especially suited to immunize against mutant HIV viruses, but also against other viruses, e.g. mutated hepatitis B viruses.
For purposes of immunization, the amino acid sequence may be a component of a peptide or protein. The peptide or protein may be coupled to a lipopeptide or lipoprotein, preferably tripalmitoyl-S-glyceryl-cysteinyl-Beryl-serine. Depending on the purpose, the peptide or protein may be contained within a liposome or ISCOM (immunostimulatory complex). The peptide or protein may however also be coupled to a viral protein which preferably is selected from the following group: HIV virus-like particles, HIV gag particles, or HBs antigens.
This peptide may preferably be present as a peptide-HLA
complex in soluble form, e.g. as HLA-A2 tetramer. The above-mentioned complex may be bound to a liposome. The peptide may however also be part of a cell presenting an antigen, preferably a dendritic cell, macrophage, B cell, or CD4+ T
cell. This may be achieved both by exogenic addition of the peptide to the cell and endogenic processing of proteins expressed in the cell.
According to the invention, this medicament may further contain cytokines such as interleukin-2 and/or GM-CSF, or polyvalent vaccines. It has proven especially beneficial to select the amino acid sequence from among the following sequences:
IVIYQYVDDL(SEQ ID N0:1), IVICQYVDDL (SEQ ID N0:2), IVIYQYIDDL(SEQ ID N0:3), IVICQYIDDL (SEQ ID N0:4), ITIYQYVDDL(SEQ ID N0:5), ITICQYVDDL (SEQ ID N0:6), ITIYQYIDDL(SEQ ID N0:7), ITICQYIDDL (SEQ ID N0:8), IIIYQYVDDL(SEQ ID N0:9), IIICQYVDDL (SEQ ID NO:10) IIIYQYIDDL(SEQ ID N0:11), IIICQYIDDL (SEQ ID N0:12), MVIYQYVDDL(SEQ ID N0:13), MVICQYVDDL (SEQ ID N0:14), MVIYQYIDDL(SEQ ID N0:15), MVICQYIDDL (SEQ ID N0:16), VIYQYVDDL (SEQ ID N0:17), VICQYVDDL (SEQ ID N0:18), VIYQYIDDL (SEQ ID N0:19), VICQYIDDL (SEQ ID N0:20), LIYQYVDDL (SEQ ID N0:21), LICQYVDDL (SEQ ID N0:22), LIYQYIDDL (SEQ ID N0:23), LICQYIDDL (SEQ ID N0:24), TILQYVDDILL Q ID N0:25), TICQYVDDILL
(SE (SEQ ID
N0:26), ILQYVDDIL (SEQ ID N0:27), ILQYIDDIL (SEQ ID N0:28), TIVQYVDDILL TIVQYIDDILL
(SEQ ID (SEQ ID
N0:29), N0:30), IVQYIDDIL (SEQ ID N0:31), IVQYIDDIL (SEQ ID N0:32), ILVQYVDDIL(SEQ ID N0:33), ILVQYIDDIL (SEQ ID N0:34), IIIQYVDDIL(SEQ ID N0:35), IIIQYIDDIL (SEQ ID N0:36), ILIQYVDDIL(SEQ ID N0:37), ILIQYIDDIL (SEQ ID N0:38), VLYQYVDDL (SEQ ID N0:39), VLCQYVDDL (SEQ ID N0:40), VLYQYIDDL (SEQ ID N0:41), VLCQYIDDL (SEQ ID N0:42), where V = valine, I - isoleucine, L = leucine, M =
methionine, C = cysteine, and Q = glutamine. The nucleic acid sequence may be a DNA or RNA sequence. It is possible for the nucleic acid sequence to be a component of a plasmid or viral vector, preferably of a recombinant vaccinia virus or recombinant adenovirus, or a retroviral vector. The nucleic acid sequence may also be a component of retroviral vectors or attenuated retroviruses. Furthermore, the nucleic acid may be a component of a bacterial vector, preferably a recombinant BCG or salmonella vector or inactivated virus, preferably HIV virus. According to the invention, the medicament may also be used in the ex vivo production of T
cells or T cell receptors.
An additional object of the present invention is the use of a medicament according to the present invention for prevention or treatment of viral infection, preferably involving mutated HIV, HIV-1, HIV-2, HTLV-I, or HTLV-II viruses, or mutated hepatitis B viruses. The viruses may also be mutated viruses resistant to (-)-2',3'-dideoxy-3'-thiacytidine [3TC
(lamivudine)], (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]-2-cyclopentene-1-methanol [abacavir], 2',3'-dideoxyinosine [didanosin], 2',3'-dideoxycytidine [zalcitabin], (-)-2'-deoxy-5-fluoro-3'-thiacytidine [FTC].
The efficacy of the medicament of this invention is, for example, explained using a graphic representation of experimental results. The following is shown here:
Fig. 1 recognition of CTL epitope VIYQYVDDL (SEQ ID N0:17) or VIYQYIDDL (SEQ ID N0:19) by CTL clone ETMV1 and non-recognition of CTL epitope VIYQYMDDL described above by the same clone, Fig. 2 specific lysis of clone of ETMV1 during titration of peptides VIYQYVDDL (SEQ ID N0:17) and VIYQYIDDL
(SEQ ID N0:19), Fig. 3 recognition of peptide VIYQYVDDL (SEQ ID N0:17), and Fig. 4 non-recognition of peptides VIYQYVDDL (SEQ ID
N0:17) and VIYQYIDDL (SEQ ID N0:19) by CTL clone EB3, which recognizes the wild-type sequence VIYQYMDDL.
In Fig. 1, the peptides were pre-incubated at a concentration of 1 ~Cg/ml for one hour with autologous EBV transformed B-cell lines labelled with 5lchromium. Four hours after addition of clone ETMVl with an effector-target ratio of 15:1, the supernatant was harvested and the specific lysis was calculated based on the amount of chromium released. The p17-peptide KIRLRPGGK was used as control. As can be inferred from Fig. 1, only peptides IVIYQYVDDL (SEQ ID NO:1), VIYQYVDDL (SEQ ID N0:17), and VIYQYIDDL (SEQ ID N0:19) were recognized, which contain resistance mutations against reverse transcriptase inhibitors. Wild-type peptide VIYQYMDDL was not recognized.
In order to achieve the results represented in Fig. 2, the peptides described therein were pre-incubated for one hour at concentrations as indicated with autologous EBV-transformed B-cell lines labelled with 5lchromium. Four hours after addition of clone ETMV1 with an effector-target ratio of 5:1, the supernatant was harvested and the specific lysis was calculated based on amounts of chromium released.
Fig. 3 indicates recognition of peptide VIYQYVDDL (SEQ ID
N0:17) (=RT50 M/V). It is HLA-A2 restricted. The shown results were achieved by pre-incubating the peptide and control peptide for one hour at a concentration of 10 ug/ml with autologous EBV-transformed B-cell lines labelled with 5lchromium, HLA-A2-matched, or HLA-A2-negative allogenic B-cell lines. Four hours after addition of clone ETMV1 with an effector-target ratio of 5:1, the supernatant was harvested and the specific lysis was calculated based on amount of chromium released. Addition of antibodies to CD8 showed that lysis is HLA class-I restricted.
The table shown in Fig. 4 indicates recognition of variant peptides by clone EB3. For this purpose, peptides at indicated concentrations were pre-incubated for one hour with autologous EBV-transformed B-cell lines labelled with 5lchromium. Five hours after addition of clone EB3 with an effector-target ratio of 8:1 or 10:1, the supernatant was harvested and specific lysis was calculated based on amount of chromium released. This clone recognizes non-mutated wild-type sequence of HIV, but not the sequence of this invention. It is shown that the sequence of this invention is a new CTL epitope.

SEQUENCE LISTING
<110> Glaxo Group Ltd.
Harrer Dr., Thomas <120> Medicaments for inducing cytotoxic T- cells <130> 77673m3 <140> PCT/EP99/02249 <141> 1999-04-O1 <150> DE 19814925.5 <151> 1998-04-03 <160> 42 <170> PatentIn Vers. 2.0 <210> 1 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 1 Ile Val Ile Tyr Gln Tyr Val Asp Asp Leu <210> 2 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 2 Ile Val Ile Cys Gln Tyr Val Asp Asp Leu <210> 3 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of fArtificial Sequence: Peptide <400> 3 Ile Val Ile Tyr Gln Tyr Ile Asp Asp Leu <210> 4 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 4 Ile Val Ile Cys Gln Tyr Ile Asp Asp Leu <210> 5 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 5 Ile Thr Ile Tyr Gln Tyr Val Asp Asp Leu <210> 6 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 6 Ile Thr Ile Cys Gln Tyr Val Asp Asp Leu <210> 7 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 7 Ile Thr Ile Tyr Gln Tyr Ile Asp Asp Leu <210> 8 <211> 10 <212> PRT
<213> Artificial Sequence <220>

<223> Description of Artificial Sequence: Peptide <400> 8 Ile Thr Ile Cys Gln Tyr Ile Asp Asp Leu <210> 9 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 9 Ile Ile Ile Tyr Gln Tyr Val Asp Asp Leu <210> 10 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> to Ile Ile Ile Cys Gln Tyr Val Asp Asp Leu <210> 11 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 11 Ile Ile Ile Tyr Gln Tyr Ile Asp Asp Leu <210> 12 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 12 Ile Ile Ile Cys Gln Tyr Ile Asp Asp Leu <210> 13 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 13 Met Val Ile Tyr Gln Tyr Val Asp Asp Leu <210> 14 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 14 Met Val Ile Cys Gln Tyr Val Asp Asp Leu 1 , 5 10 <210> 15 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 15 Met Val Ile Tyr Gln Tyr Ile Asp Asp Leu <210> 16 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 16 Met Val Ile Cys Gln Tyr Ile Asp Asp Leu <210> 17 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 17 Val Ile Tyr Gln Tyr Val Asp Asp Leu <21D> 18 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> la Val Ile Cys Gln Tyr Val Asp Asp Leu <210> 19 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 19 Val Ile Tyr Gln Tyr Ile Asp Asp Leu <210> 20 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 20 Val Ile Cys Gln Tyr Ile Asp Asp Leu <210> 21 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 21 Leu Ile Tyr Gln Tyr Val Asp Asp Leu <21D> 22 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 22 Leu Ile Cys Gln Tyr Val Asp Asp Leu <210> 23 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 23 Leu Ile Tyr Gln Tyr Ile Asp Asp Leu <210> 24 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 24 Leu Ile Cys Gln Tyr Ile Asp Asp Leu <210> 25 <211> 11 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial 5equence:Peptide <400> 25 Thr Ile Leu Gln Tyr Val Asp Asp Ile Leu Leu <210> 26 <211> 11 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 26 Thr Ile Leu Gln Tyr Ile Asp Asp Ile Leu Leu <210> 27 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 27 Ile Leu Gln Tyr Val Asp Asp Ile Leu <210> 28 <211> 9 <212> P~RT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 28 Ile Leu Gln Tyr Ile Asp Asp Ile Leu <210> 29 <211> 11 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 29 Thr Ile Val Gln Tyr Val Asp Asp Ile Leu Leu <210> 30 <211> 11 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 30 Thr Ile Val Gln Tyr Ile Asp Asp Ile Leu Leu <210> 31 <211> 9 <212> PRT
<213> Artificial Sequence <220>

~

<223> Description of Artificial Sequence: Peptide <400> 31 Ile Val Gln Tyr Ile Asp Asp Ile Leu <210> 32 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 32 Ile Val Gln Tyr Ile Asp Asp Ile Leu <210> 33 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 33 Ile Leu Val Gln Tyr Val Asp Asp Ile Leu <210> 34 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 34 Ile Leu Val Gln Tyr Ile Asp Asp Ile Leu <210> 35 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 35 Ile Ile Ile Gln Tyr Val Asp Asp Ile Leu <210> 36 <211> 10 <212> PRT
<213> Artificial Sequence <22D>
<223> Description of Artificial Sequence: Peptide <400> 36 Ile Ile Ile Gln Tyr Ile Asp Asp Ile Leu <210> 37 <211> 10 <212> PRT
<213> Artificial Sequence <22D>
<223> Description of Artificial Sequence: Peptide <4DD> 37 Ile Leu Ile Gln Tyr Val Asp Asp Ile Leu <210> 38 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 38 Ile Leu Ile Gln Tyr Ile Asp Asp Ile Leu <210> 39 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 39 Val Leu Tyr Gln Tyr Val Asp Asp Leu <210> 40 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 40 Val Leu Cys Gln Tyr Va 1 Asp Asp Leu <210> 41 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Description of Artificial Sequence: Peptide <400> 41 Val Leu Tyr Gln Tyr Ile Asp Asp Leu <210> 42 <211> 9 <212> PRT
<213> Artif_cial Sequence <220>
<223> Descr_ption of Artificial Sequence: Peptide <400> 42 Val Leu Cys Gln Tyr Ile Asp Asp Leu

Claims (29)

Claims
1. A compound containing or consisting of an amino acid or nucleic acid encoding said amino acid, wherein said amino acid has the following sequence:

X1-Y-X2-D-D-X3, wherein Xl - at least one of any amino acid Y - tyrosine X2 = one amino acid selected from the following group:
valine, isoleucine, and leucine D = aspartate, and X3 = at least one of any additional amino acid, except for the following amino acid sequences:
LRVEYLDDR, TLVLQYVDDLLL, and ILVLQYVDDLLL, with T = threonine, V = valine, I = isoleucine, L = leucine, Q = glutamine, and R = arginine.
2. A compound according to claim 1, wherein said amino acid sequence consists of nine amino acids.
3. A compound according to any one of the preceding claims, wherein X1 is a sequence consisting of four or five amino acids.
4. A compound according to any one of the preceding claims, wherein X3 is a sequence consisting of one or two additional amino acids.
5. A compound according to any one of the preceding claims, wherein said amino acid sequence is a component of a peptide.
6. A compouna according to any one of the preceding claims, wherein said amino acid sequence is a component of a protein.
7. A compound according to any one of the preceding claims, wherein said peptide or protein is coupled to a lipopeptide or lipoprotein, preferably to tripalmitoyl-S-glycerylcysteinyl-seryl-serine.
8. A compound according to any one of the preceding claims, wherein said peptide or protein is contained within a liposome or ISCOM.
9. A compound according to any one of the preceding claims, wherein said peptide or protein is coupled to a viral protein.
10. A compound according to any one of the preceding claims, wherein said peptide is selected from the following group: HIV virus-like particles, HIV gag-particles, or HBs antigens.
11. A compound according to any one of the preceding claims, wherein said peptide is present as a soluble peptide-HLA
complex, preferably as a HLA-A2 tetramer.
12. A compound according to any one of the preceding claims, wherein said peptide is present as a soluble peptide-HLA
complex bound to a liposome.
13. A compound according to any one of the preceding claims, wherein said peptide is a component of an antigen-presenting cell, preferably dendritic cell, macrophage, B cell or CD4+ T cell.
14. A compound according to any one of the preceding claims, wherein said amino acid sequence is selected from among the following amino acid sequences:

IVIYQYVDDL (SEQ ID NO:1), IVICQYVDDL (SEQ ID NO:2), IVIYQYIDDL (SEQ ID NO:3), IVICQYIDDL (SEQ ID NO:4), ITIYQYVDDL (SEQ ID NO:5), ITICQYVDDL (SEQ ID NO:6), ITIYQYIDDL (SEQ ID NO:7), ITICQYIDDL (SEQ ID NO:8), IIIYQYVDDL (SEQ ID NO:9), IIICQYVDDL (SEQ ID NO:10) IIIYQYIDDL (SEQ ID NO:11), IIICQYIDDL (SEQ ID NO:12), MVIYQYVDDL (SEQ ID NO:13), MVICQYVDDL (SEQ ID NO:14), MVIYQYIDDL (SEQ ID NO:15), MVICQYIDDL (SEQ ID NO:16), VIYQYVDDL (SEQ ID NO:17), VICQYVDDL (SEQ ID NO:18), VIYQYIDDL (SEQ ID NO:19), VICQYVDDL (SEQ ID NO:20), LIYQYVDDL (SEQ ID NO:21), LICQYVDDL (SEQ ID NO:22), LIYQYIDDL (SEQ ID NO:23), LICQYIDDL (SEQ ID NO:24), TILQYVDDILL (SEQ ID NO:25), TICQYVDDILL (SEQ ID NO:26), ILQYVDDIL (SEQ ID NO:27), ILQYIDDIL (SEQ ID NO:28), TIVQYVDDILL (SEQ ID NO:29), TIVQYIDDILL (SEQ ID NO:30), IVQYIDDIL (SEQ ID NO:31), IVQYIDDIL (SEQ ID NO:32), ILVQYVDDIL (SEQ ID NO:33), ILVQYIDDIL (SEQ ID NO:34), IIIQYVDDIL (SEQ ID NO:35), IIIQYIDDIL (SEQ ID NO:36), ILIQYVDDIL (SEQ ID NO:37), ILIQYIDDIL (SEQ ID NO:38), VLYQYVDDL (SEQ ID NO:39), VLCQYVDDL (SEQ ID NO:40), VLYQYIDDL (SEQ ID NO:41), VLCQYIDDL (SEQ ID NO:42), where C = cysteine, D = aspartate, I = isoleucine, L =
leucine, M = methionine, and Q = glutamine.
15. A compound according to any one of the preceding claims, wherein said nucleic acid sequence is a DNA or RNA
sequence.
16. A compound according to any one of the preceding claims, wherein said nucleic acid sequence is a component of a plasmid or viral vector, preferably a recombinant vaccinia virus, adenovirus, or retroviral vector.
17. A compound according to any one of the preceding claims, wherein said nucleic acid sequence is a component of a bacterial vector, preferably of a recombinant BCG or salmonella vector.
18. A compound according to any one of the preceding claims, wherein said nucleic acid sequence is a component of an inactivated virus, preferably an inactivated HIV virus.
19. A medicament containing as active ingredient a compound according to any one of the preceding claims.
20. A medicament according to claim 19 in form of a vaccine.
21. A medicament according to claim 20 containing polyvalent vaccines.
22. A medicament according to any one of claims 19 through 21, wherein one or more cytokines are contained as adjuvant.
23. A medicament according to any one of claims 19 through 22, wherein interleukin-2 and/or GM-CSF are contained as adjuvant.
24. A method for the prevention or treatment of infections with viruses, preferably mutated HIV, HIV-l, HIV-2, HTLV-I, and HTLV-II viruses or mutated hepatitis B
viruses or a disease responding to induction of cytotoxic T cells, consisting of administering to patient an effective dose of a medicament comprising a peptide of the following sequence:

X1-Y-X2-D-D-X3, wherein X1 = at least one of any amino acid Y = tyrosine, X2 = one amino acid selected from the following group:
valine (V), isoleucine (I), and leucine (L), D = aspartate, and X3 = at least one additional of any amino acid, or a nucleic acid encoding said peptide.
25. A method according to claim 24, wherein said mutant viruses are resistant to reverse transcriptase inhibitors.
26. A method according to claim 24 or 25, wherein said mutant viruses are resistant to (-)-2',3'-dideoxy-3'-thiacytidine [=3TC (lamivudine)] , (-)-(1S,4R) -4- [2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol [abacavir], 2',3'-dideoxyinosine [didanosin], 2',3'-dideoxycytidine [zalcitabin], (-)-2'-deoxy-5-fluoro-3'-thiacytidine [=FTC].
27. A use of the following amino acid sequence:

X1-Y-X2-D-D-X3, wherein X1 = at least one of any amino acid Y = tyrosine (T), X2 = one amino acid selected from the following group:
valine (V), isoleucine (I), and leucine (L), D = aspartate, and X3 = at least one of any additional amino acid, or a nucleic acid encoding said peptide, for the preparation of a medicament for the prevention or treatment of infections with viruses, preferably mutated HIV, HIV-1, HIV-2, HTLV-I, and HTLV-II viruses or mutated hepatitis B viruses or a disease responding to induction of cytotoxic T cells.
28. A use according to claim 27, wherein said mutant viruses are resistant to reverse transcriptase inhibitors.
29. A use according to claim 27 or claim 28, wherein said mutant viruses are resistant to (-)-2',3'-dideoxy-3'-thiacytidine [=3TC (lamivudine)], (-)-(1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (abacavir], 2',3'-dideoxyinosine [didanosin], 2',3'-dideoxycytidine [zalcitabin], (-)-2'-deoxy-5-fluoro-3'-thiacytidine [=FTC].
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