WO1989002277A2 - Prophylaxie et therapie du syndrome immunodeficitaire acquis - Google Patents

Prophylaxie et therapie du syndrome immunodeficitaire acquis Download PDF

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Publication number
WO1989002277A2
WO1989002277A2 PCT/US1988/002970 US8802970W WO8902277A2 WO 1989002277 A2 WO1989002277 A2 WO 1989002277A2 US 8802970 W US8802970 W US 8802970W WO 8902277 A2 WO8902277 A2 WO 8902277A2
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human immunodeficiency
immunodeficiency virus
peptide
cell
peptides
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PCT/US1988/002970
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English (en)
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WO1989002277A3 (fr
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Ralph B. Arlinghaus
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Board Of Regents, The University Of Texas System
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/464838—Viral antigens
    • 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
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention concerns a method to prevent or treat acquired immunodeficiency syndrome (AIDS) and involves a new and novel approach for making a vaccine.
  • the vaccine comprises synthetic peptides which exhibit certain immunologicar characteristics of one or more proteins encoded by the viral causative agent of this disease.
  • AIDS was first recognized in the United States in 1981; the number of cases has been increasing at a dramatic pace since then. Since 1978 more than 2.4 million AIDS infections have been reported in the United States, alone (Rees, Nature, 326:343, 1987). Once significant immunosuppressive symptoms appear in an infected individual, the expected outcome of the infection is death. There is currently no known treatment that can indefinitely delay or prevent the fatal consequences of the disease. Although the disease first manifested itself in homosexual or bisexual males and intravenous drug abusers, it has now spread to others by means such as intimate sexual contact with or receipt of blood products from a carrier of the virus.
  • the causative agent, associated with AIDS has been identified as a group of closely related retroviruses commonly known as Human T Cell Lymphotrophic Virus-type III (HTLV-III), Lymphoadenopathy Viruses (LAV), AIDS-Related Viruses (ARV), or more recently named Human Immunodeficiency Virus (HIV). These viruses will be collectively referred to herein for convenience as HIV.
  • HTLV-III Human T Cell Lymphotrophic Virus-type III
  • LAV Lymphoadenopathy Viruses
  • ARV AIDS-Related Viruses
  • HIV Human Immunodeficiency Virus
  • HIV has RNA as its genetic material.
  • a viral enzyme known as reverse transcriptase copies the viral RNA into a double stranded DNA.
  • the viral DNA migrates to the nucleus of the cell where it serves as a template for additional copies of viral RNA which can then be assembled into new viral particles.
  • the viral RNA can also serve as messenger RNA for certain viral proteins [either the viral core proteins (known as p18, p24 and p13)] or the reverse transcriptase, or be "spliced" into specific viral messenger RNAs necessary to produce several other viral proteins including two glycosylated structural proteins known as gp41 and gp120 which are inserted in the outer membrane of the virus (Wain-Hobson et al., Cell 40:9, 1985).
  • gp41 and gp120 two glycosylated structural proteins known as gp41 and gp120 which are inserted in the outer membrane of the virus.
  • purified gp120 induces antibody in the goat, horse and rhesus monkey that neutralizes HIV in lab tests (Robey et al., Proc. Natl. Acad. Sci., USA 83:7023, 1986).
  • Vaccines have been used for many years to prevent infections caused by agents such as viruses.
  • the general approach has been to inject healthy individuals with, for example, a killed or modified virus preparation in order to prime the individual's immune systems to mount an assault on the infecting virus.
  • Recent advances in recombinant DNA technology have allowed safer methods of vaccination that involve use of exposed viral components produced by microbial systems.
  • the viral component for example a protein subunit, is administered as a vaccine in a suitable vehicle and/or an adjuvant. The latter stimulates the host's system in a way that improves the immune response to the viral subunit.
  • Another potential method of making a vaccine is by using chemically synthesized peptide fragments of a viral protein subunit. This method has several advantages over the other methods of producing vaccines, including purity of the product, reproducibility and specificity of the immune response.
  • mice A short peptide region within the surface protein of infectious Hepatitis B virus has been shown to elicit only a T cell response in mice (Milich et al., 1986). Specifically, a synthetic peptide, whose sequence is derived from amino acids numbered 120-132 located within the pre-S(2) domain of the Hepatitis B surface antigen gene, elicited a very strong T cell priming response to the peptide but stimulated only a very weak antibody response. In other words, mice mounted a poor antibody response to that peptide, but the T cells of immunized mice were efficiently primed (i.e. activated) to recognize that peptide as measured in T cell proliferation assays (Milich et al., 1986). The low level of the antibody produced by mice immunized with this peptide did not bind to the native viral surface antigen.
  • the sequence of this T cell active peptide is:
  • A alanine
  • C cysteine D
  • D glutamic acid
  • F phenylalanine
  • G glycine
  • H histidine
  • I isoleucine
  • K lysine
  • L leucine
  • M methionine
  • N asparagine
  • P proline
  • Q glutamine
  • R arginine
  • S serine
  • T threonine
  • V valine
  • W tryptophan
  • Y tyrosine.
  • the sequence of the second or B cell active peptide is:
  • mice were also immunized with a longer peptide made up of both of the above-mentioned T- and B-active peptide sequences. In this case high titers of antibody were produced against the B site peptide but not the T site peptide.
  • the combination of both T- and B-sites within one peptide should stimulate both T and B cell responses, as measured by producing a specific antibody to the B cell epitope of the peptide chain.
  • Synthetic peptide antigens may be constructed to produce two types of immune responses: T-cell only and T cell combined with a B cell response.
  • the present invention involves a process for inducing resistance of an individual to infection by human immunodeficiency virus.
  • the process involves vaccinating said individual with a synthetic peptide or mixtures of synthetic peptides.
  • the synthetic peptide(s) comprises an amino acid sequence derived at least in part from human immunodeficiency virus envelope protein conserved region. Upon antigenic presentation, such a peptide induces directed cell-mediated immunity (i.e. T-cell cytotoxicity) to a substantially greater extent than production of antibody directed against native human immunodeficiency virus is elicited.
  • the vaccine of the present invention comprises a synthetic peptide (s) having an amino acid sequence derived at least in part from T-cell epitopes of human immunodeficiency virus envelope protein conserved region and preferably consists exclusively of T cell epitopes.
  • the invention further predicts that the chemical nature and properties of the HIV surface proteins are similar to or may resemble proteins products of the immunoglobulin gene family in one or more biological characteristics.
  • This group of genes includes the various immunoglobulins, the T cell receptor protein involved in antigen recognition, the major histocompatibility genes, the T4 antigen and others. This similarity will likely render HIV resistant to vaccines that induce an antibody response.
  • HTLV-1 Human T Cell Leukemia virus type 1
  • FeLV Feline Leukemia virus
  • HTLV-1 is associated with a T cell malignancy known as Adult T cell Leukemia (Yoshida and Seiki, Ann. Rev. Immunol 5:541, 1987). It is likely then that the surface proteins of both of these viruses also share one or more biological properties with the protein products of the immunoglobulin gene family and therefore will be resistant to vaccines that depend on antibody-induced inactivation of the infectious virus.
  • the process of the present invention for inducing resistance to human immunodeficiency virus comprises several steps.
  • Amino acid sequences of human immunodeficiency virus envelope protein conserved region able to form helical structures and further characterized by the presence of amphipathically interrelated amino acids are first identified.
  • Peptides or peptide derivatives comprising at least a substantial part of the identified sequences are then synthetically prepared.
  • Said peptides or peptide derivatives are then administered to a test animal in a manner stimulating an immune response.
  • the T cell response and humoral antibody response in said test animal are monitored to screen for peptides or peptide derivatives which stimulate T-cell immunity without inducing substantial production of humoral antibody directed against native human immunodeficiency virus.
  • An individual is then inoculated with an immunogenic composition comprising said screened peptide or peptide derivative to induce resistance to human immunodeficiency virus infection.
  • the peptides or peptide derivatives of the present invention useful in prophylaxis of AIDS preferably comprise an amino acid sequence of human immunodeficiency virus envelope glycoproteins' conserved regions.
  • the human immunodeficiency virus envelope glycoproteins includes human immunodeficiency virus glycoprotein gp 120 and human immunodeficiency virus glycoprotein gp 41.
  • HIV-infected cells may express, on their surface, T cell epitopes of HIV envelope proteins and/or HIV core proteins.
  • an immunizing peptide or peptide derivative may have an amino acid sequence substantially comprising one or more T cell epitopes of a HIV envelope protein or HIV core protein.
  • the synthetic peptides of the present invention may be prepared by techniques involving solid-phase chemical synthesis, liquid-phase chemical synthesis or biological synthesis involving recombinant DNA, all well-known to those skilled in the relevant arts.
  • the HIV agent is unique in that it infects cells involved in the immune response and can kill these cells.
  • the host cell often involved is the T4 lymphocyte, a white blood cell that plays a central role in regulating the immune system.
  • the virus binds to cell surface T4 protein which is implicated in the mediation of efficient T cell-target cell interactions.
  • T4+ lymphocytes interact with target cells expressing major histocompatibility (MHC) class II gene products. Both T4 and MHC genes are members of the immunoglobulin gene family (Maddon et al., Cell, 47:333, 1986).
  • MHC major histocompatibility
  • gp120 two regions of gp120 were found to share sequence homology with human immunoglobulin heavy chain constant regions (Maddon et al., Cell, 47:333, 1986). Extrapolating from these observations, the present invention may hinge upon the fact that gp120 has certain properties unique to human immunoglobulins. Furthermore, this similarity in structure may allow the virus to escape inactivation by antibody interaction. Furthermore, viral-antibody interaction may, in certain situations, increase the infectivity of the virus. Recent work suggests that AIDS patients can and do have antibodies that neutralize the virus, as determined by in vitro lab tests. Yet these same patients die of the disease.
  • the present invention predicts that antibodies binding to the virus may not interfere with and in some cases may even increase the virus' inherent ability to infect the patient's lymphoid cells. Recently retrovirus infectivity was shown to be increased by binding of anti-retrovirus antibodies (Legrain et al., J. Virol., 60:1141, 1986). Therefore, an AIDS vaccine that primes the individual's immune system to make antibodies to viral surface proteins may enhance the infectivity of an already deadly virus. What is needed then is to stimulate only the individual's T cell immunity (for example, cytotoxic T cells or CD8+ T cells) without involving an antibody response to viral proteins.
  • T cell immunity for example, cytotoxic T cells or CD8+ T cells
  • Synthetic peptide immunogens can certainly achieve this result.
  • the vaccine of the present invention is preferably a totally synthetic vaccine made using a synthetic peptide(s) linked to a fatty acid compound, or polymerized through natural or extra cysteine residues. Important facets or considerations may be listed as follows for a vaccine of the present invention.
  • the vaccine of the present invention comprises short synthetic peptides. These short synthetic peptides (10-30 amino acids in length) have sequences from one or more conserved regions of either of the two HIV envelope. These peptides should elicit a T cell response but not a substantial antibody response. Therefore, when suitably prepared, the peptide vaccine of the present invention will stimulate T cell immunity (i.e., cytotoxic T cells) without producing a substantial humoral antibody response.
  • the peptide-vaccine of the present invention should prime T cells in a way that, when the infecting virus appears at a later date, memory T cells will be activated to result in a cell-mediated immune response that will destroy the virus.
  • an effective peptide may in some cases induce a low to moderate level antibody response and still be useful as an effective vaccine.
  • the induced anti-peptide antibodies must be incapable of recognizing or detecting the mature protein from which the vaccinating peptide was derived.
  • the anti-peptide antibody induced by the T cell active peptide must not be substantially capable of binding to the intact, infectious virus. It is well known that antipeptide antibodies to certain regions of a given protein may not recognize the native protein (for example, see the work of Ho et al., J. Virol., 61:2024, 1987).
  • the first step in preparation of the vaccine of the present invention is to prepare a number of peptides 10-30 amino acids in length and having an amino acid sequence derived from the two envelope proteins or their genes. conserveed protein sequence regions of each envelope protein will be selected for investigation. For example, a large portion of gp41 is conserved among the seven strains of HIV-sequenced to date (Modrow et al., J. Virol., 61:570, 1987).
  • Short synthetic peptides are made from predicted T cell regions.
  • T cell epitopes were selected from a first conserved segment of gpl20 (Modrow et al., J. Virol., 61:570-578). Their sequences are as follows, with the amino terminus at the left and carboxy terminus on the right, in standard fashion:
  • T cell epitopes are predicted T cell epitopes within a 100 amino acid stretch of conserved sequences near the amino terminus of the gp120 protein. A recent report indicated that this region is active in stimulating T cell immunity (Ahearne et al., III International Conference on AIDS, held in Washington, D.C., June 1-5, 1987, abstract # M.10.3, page 8).
  • Antigenic sites recognized by T cells have been reported to correlate with helical structures (either alpha helices or another type helix called a 3 10 helical structure). Such antigenic sites are also thought to be protein segments displaying a polar/apolar character, forming a stable amphipathic structure with separated hydrophobic and hydrophilic surfaces and/or protein segments displaying a marked change in hydrophilicity between the first-half and the second-half of a block of amino acids (differential amphipathic structures).
  • the helical structures are identified by a consistent stretch of blocks of amino acids (each block being 6-7 residues in length) with angles (termed delta values) of 100' ⁇ 20' (alpha helix) or 120' ⁇ 15' (3 10 helical structure).
  • Differential amphipathic structures are identified by peaks of differential hydrophilicity (See Table 1). For the purpose of selecting regions that are predicted to be poor antibody eliciting and/or binding sites, these structures should have negative mean hydrophilicity values. All of these values are listed below in Table 1 as the computer analysis of a conserved gp120 sequence (residues 35-137).
  • peptides were selected from within residues 35 through 137 of the gp120 surface protein of HIV.
  • Peptide number (1) which spans blocks 1-5 (6 amino acids per block) has delta values (termed ANGLE) consistent with a helical structure as predicted by both the Hopp/Woods computer program (block length of 6 amino acids) and the Kyte/Doolittle computer program (block length of 7 amino acids).
  • Peptide number (2) which spans blocks 23-28 has a peak of differential hydrophilicity (a marked change in mean hydrophilicity between the first-half and second-half of a block of amino acids) that is predicted by both programs.
  • Peptide number (3) which spans blocks 56-63 has delta values consistent with a helical structure (Kyte/Doolittle) and a peak of hydrophilicity (both programs).
  • Peptide number (4) which spans blocks 76-83 has a peak of differential hydrophilicity (both programs).
  • Peptide number (5) which spans blocks 87-94 has delta values consistent with. helical structures (both programs).
  • T cell active peptides it may be necessary to thoroughly cover the protein sequence in question.
  • overlapping 15-amino acid peptides (15 mers) can be made (the second peptide overlaps with the C-terminal 5 amino acids of the first peptide, the third overlaps the second, etc.) across the complete conserved amino acid sequence of both gp120 and gp41.
  • each peptide is linked to a dipalmityl-lysyl-glycyl-glycyl sequence to serve as a carrier as described by T.P. Hopp (Mol. Immunol., 21:13, 1984).
  • peptides can be made without the use of the dipalmitate carrier and otherwise tested.
  • peptides containing two natural cysteines as part of their natural sequence may be selected and synthesized.
  • Peptides lacking such cysteines can be modified by the addition of extra cysteines to the N- and C-terminal ends, respectively.
  • the presence of two cysteines per peptide allow polymerization of the subunit peptide by air oxidation to form cysteine-linked polymers and/or cyclic peptides. Such polymers should enhance immune recognition of the peptide without the need of a carrier.
  • T cell active peptides will be assayed by injecting the peptide into mice, and then testing T cells recovered from the murine lymph nodes one to three weeks after inoculation with the peptide. The measurement of activation or priming of T cells will be done by T cell proliferation tests and/or interleukin-2 production (Milich et al., J. Exp. Med., 164:532, 1986). Two types of T cell active peptides should be found. The more prevalent group of peptides will prime T cells that respond in test tube assays to only the peptide and not the corresponding native HIV surface protein.
  • the second group of peptides will prime T cells to respond to both the peptide and the native HIV protein. It is this latter group of peptides that will induce protective immunity in the vaccinated host. Several strains of mice will be used which vary in their histocompatibility genes. Peptides that have a broad response in the various MHC genotypes will be selected for further study in primates, finally humans.
  • T cell active peptides will then be screened to identify those peptides that lack B cell stimulatory activity. This will be accomplished by injecting each peptide into small animals (various strains of mice) to identify those peptides that fail to generate an antibody response. These animals should not produce anti-peptide antibodies binding to native viral proteins. These same selected peptides will be tested in baboons and monitored to confirm the lack of anti-peptide antibody production in baboon sera. At this stage, mixtures of peptides will be employed because it is quite possible that one peptide sequence will not provide the broad spectrum coverage needed for an effective vaccine. Candidate peptide mixtures will then be incorporated into a vaccine.
  • Candidate peptide mixtures will then be tested in a suitable animal that allows replication of the AIDS virus (Chimpanzees) to test for priming of T cells. Peptides that are more active will be used to vaccinate chimpanzees in a virus challenge experiment. A successful protection experiment will prevent viremia without eliciting a significant humoral antibody response but will prime T cells for in vitro responses to the envelope antigens. The virus will be neutralized by cell mediated immunity.
  • the present invention involves the prediction that antibody responses to most if not all surface antigen epitopes will increase or at least not impede the infectivity of the AIDS virus.
  • the anti- peptide antibody must not be capable of recognizing the native envelope proteins as measured, for example, either by immunoblotting procedures or by other immunoabsorbent (ELISA) tests. What is important in this particular response is that anti-peptide antibodies against a certain peptide sequence must not induce antibodies that bind to the infectious virus. Thus, in this case, T cell active peptides that raise low or moderate levels of anti-peptide antibodies will be screened to identify those that fail to detect either intact virus preparations or viral surface proteins by immunoabsorbent tests (ELISA) and/or immunoblot procedures.
  • ELISA immunoabsorbent tests
  • the synthetic vaccine of the present invention will focus on peptides sequences predicted from one of the viral surface proteins in order to prevent virus infection of the exposed individual, this approach might also be used to treat individuals who are already infected with HIV.
  • the target for cell-mediated immunity includes not only the virus but more importantly the virus-infected cell.
  • Infected cells will have not only viral envelope proteins on their surfaces but possibly glycosylated core proteins (gag gene products) or their higher molecular weight precursors as well (Naso et al., J. Virol., 45:1200, 1983). Therefore, T cell active peptides from the gag gene of HIV can also be selected and tested for their affects on virus infected cells.
  • gag gene of HIV has revealed several T cell epitopes from within the core or gag gene of HIV (Coates et al., Nature, 326:549. 1987).
  • KTILKALGPA 346 355 EMMTACQGV 367 375 AEAMSQVTN
  • Such synthetic peptides should be able to induce a cell-mediated response sufficient to destroy virus-infected cells bearing the expected epitopes, or as suggested by the work Walker et al., (Science, 234:1563-1566, 1986) inhibit the growth of the virus.
  • T helper cell independent cytotoxic T cell response described by Buller et al., bodes well for the use of T cell active peptides in the therapy of AIDS.
  • Such a peptide or mixture of peptides would be expected to mount an effective cell mediated immune response at a time when T4 cells are being infected and killed by the HIV.
  • T8 cells are resistant to HIV infection, the proposed peptide(s) (either polymerized or coupled to fatty acids as described in a previous section) should activate and prime T8 cytotoxic cells allowing a specific virus-killing response in the AIDS patient even though the virus may be infecting and altering the immune helper function of T4 cells.

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Abstract

La présente invention se rapporte à un procédé servant à produire chez un individu une résistance à l'infection par le virus d'immunodéficience humain. Ledit procédé consiste à vacciner l'individu avec un peptide ou un mélange de peptides synthétiques. Le ou les peptides synthétiques comprennent une séquence d'acides aminés obtenus au moins en partie à partir d'une région conservée d'une protéine d'enveloppe du virus d'immunodéficience humain. Sur présentation sous forme antigénique à un animal, ce peptide induit une immunité véhiculée par lymphocytes dirigée (par exemple une cytotoxicité de lymphocytes T) dans une mesure sensiblement plus grande par rapport à la production d'anticorps dirigée contre le virus d'immunodéficience humain natif qu'il engendre. Le vaccin de la présente invention comprend un peptide synthétique ayant une séquence d'acides aminés obtenue au moins en partie à partir d'épitopes de lymphocytes T d'une région conservée d'une protéine d'enveloppe du virus d'immunodéficience humain et se compose de préférence exclusivement d'épitopes de lymphocytes T.
PCT/US1988/002970 1987-08-28 1988-08-26 Prophylaxie et therapie du syndrome immunodeficitaire acquis WO1989002277A2 (fr)

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Cited By (24)

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FR2650954A1 (fr) * 1989-08-18 1991-02-22 Pasteur Institut Composition resultant de la reunion d'un epitope b de la glycoproteine d'enveloppe d'un retrovirus du type iv et d'un epitope t issu d'une proteine distincte codee par ce retrovirus et leur application a la production d'anticorps protecteurs contre le sida
EP0431327A1 (fr) * 1989-11-10 1991-06-12 Hoechst Aktiengesellschaft Vaccin synthétique pour l'induction spécifique des lymphocytes-T-cytotoxiques
WO1991009869A1 (fr) * 1990-01-05 1991-07-11 Medical Research Council Fragments de la proteine du noyau de vih-1
WO1991015512A2 (fr) * 1990-04-03 1991-10-17 Genentech, Inc. Polypeptides d'enveloppe du vih
WO1991009872A3 (fr) * 1989-12-13 1992-04-02 Univax Biolog Inc Polypeptides selectivement reactifs avec des anticorps contre le virus d'immunodeficience humaine et vaccins comprenant les polypeptides
EP0491861A1 (fr) * 1989-09-20 1992-07-01 Board Of Regents, The University Of Texas System Prophylaxie et therapie du syndrome d'immunodeficience acquise
EP0491844A1 (fr) * 1989-09-19 1992-07-01 Medimmune, Inc. Peptides comprenant des epitopes ctl de proteines hiv et leur utilisation
WO1993010816A1 (fr) * 1991-12-02 1993-06-10 Board Of Regents, The University Of Texas System Compositions pour declencher des reactions de lymphocytes t cytotoxiques contre des virus
EP0601108A1 (fr) * 1991-08-29 1994-06-15 THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by the SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES Antigenes peptidiques multideterminants qui stimulent la reponse des lymphocytes t auxiliaires au vih chez des sujets humains
WO1995018148A1 (fr) * 1993-12-28 1995-07-06 Chiron Mimotopes Pty Ltd Epitopes de cellules t
WO1995020162A1 (fr) * 1994-01-19 1995-07-27 The Government Of The United States Of America, Represented By The Secretary Of The Department Of Health And Human Services Peptomeres a immunogenicite accrue
US5683701A (en) * 1988-06-10 1997-11-04 United Biomedical, Inc. Peptide fragments of HIV
US5939074A (en) * 1986-12-30 1999-08-17 The United States Of America As Represented By The Department Of Health And Human Services Multideterminant peptide antigens
US6024964A (en) * 1985-06-24 2000-02-15 Hoechst Aktiengesellschaft Membrane anchor/active compound conjugate, its preparation and its uses
US6074650A (en) * 1985-06-24 2000-06-13 Hoechst Aktiengesellschaft Membrane anchor/active compound conjugate, its preparation and its uses
US6537967B1 (en) * 2001-09-06 2003-03-25 Tripep Ab Pentamer peptide amide, ALGPGNH2, which inhibits viral infectivity and methods of use thereof
US6602705B1 (en) 1998-12-31 2003-08-05 Chiron Corporation Expression of HIV polypeptides and production of virus-like particles
US6689879B2 (en) 1998-12-31 2004-02-10 Chiron Corporation Modified HIV Env polypeptides
US7211659B2 (en) 2001-07-05 2007-05-01 Chiron Corporation Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
US7282364B2 (en) 2001-08-31 2007-10-16 Novartis Vaccines And Diagnostics, Inc. Polynucleotides encoding antigenic HIV type B polypeptides, polypeptides and uses thereof
US7803524B2 (en) 1994-02-23 2010-09-28 Siemens Healthcare Diagnostics Products Gmbh Antigenic HIV gp41 chimeric polypeptides comprising the MVP5180/91 epitope SKGKLIS
US7935805B1 (en) 1998-12-31 2011-05-03 Novartis Vaccines & Diagnostics, Inc Polynucleotides encoding antigenic HIV Type C polypeptides, polypeptides and uses thereof
US7943375B2 (en) 1998-12-31 2011-05-17 Novartis Vaccines & Diagnostics, Inc Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
US8263394B2 (en) 1998-12-31 2012-09-11 Novartis Vaccines & Diagnostics Inc. Polynucleotides encoding antigenic HIV type B polypeptides, polypeptides, and uses thereof

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EP0491844A1 (fr) * 1989-09-19 1992-07-01 Medimmune, Inc. Peptides comprenant des epitopes ctl de proteines hiv et leur utilisation
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