EP0491844A1 - Peptides comprenant des epitopes ctl de proteines hiv et leur utilisation - Google Patents

Peptides comprenant des epitopes ctl de proteines hiv et leur utilisation

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Publication number
EP0491844A1
EP0491844A1 EP90914632A EP90914632A EP0491844A1 EP 0491844 A1 EP0491844 A1 EP 0491844A1 EP 90914632 A EP90914632 A EP 90914632A EP 90914632 A EP90914632 A EP 90914632A EP 0491844 A1 EP0491844 A1 EP 0491844A1
Authority
EP
European Patent Office
Prior art keywords
peptide fragment
animal
ctl
cells
hiv
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90914632A
Other languages
German (de)
English (en)
Other versions
EP0491844A4 (en
Inventor
Thomas Fuerst
Scott Koenig
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
US Department of Health and Human Services
MedImmune LLC
Original Assignee
US Department of Health and Human Services
MedImmune LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by US Department of Health and Human Services, MedImmune LLC filed Critical US Department of Health and Human Services
Publication of EP0491844A1 publication Critical patent/EP0491844A1/fr
Publication of EP0491844A4 publication Critical patent/EP0491844A4/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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
    • 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
    • C12N2740/16311—Human Immunodeficiency Virus, HIV concerning HIV regulatory proteins
    • C12N2740/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • This invention relates to peptides which include a CTL epitope.
  • the peptides or derivatives thereof may be used to induce and/or augment a CTL response. More particularly, this invention relates to HIV (Human Immunodeficiency Virus) proteins and peptide fragments which include CTL epitopes, and which may be used to induce a CTL response to HIV virus.
  • HIV Human Immunodeficiency Virus
  • CMI Cell-mediated immunity
  • HIV human immunodeficiency virus
  • AIDS virus HIV vaccines and/or therapies based on the generation of passive transfer of HIV-specific antibody in the absence of cell-mediated immunity have not yielded consistent protection in primates challenged with the HIV virus.
  • HIV human immunodeficiency virus
  • interest has turned to the induction of cell-mediated immune responses to HIV and to the identification of specific epitopes of HIV proteins that stimulate a cytotoxic T lymphocyte, (or CTL) response.
  • a peptide fragment which includes an epitope which is recognized by cytotoxic T lymphocytes (CTL) induced by an HIV protein or CTL epitope thereof.
  • CTL cytotoxic T lymphocytes
  • the HIV protein is preferably an HIV-1 protein.
  • the peptide fragment is recognized by CTL induced by the NEF, GAG, or ENV protein, or a CTL epitope thereof.
  • peptide fragment means a peptide having a number of amino acid residues less than the number of amino acid residues present in the native protein which includes the CTL epitope.
  • a peptide fragment which includes an epitope which is recognized by CTL induced by an HIV protein is sometimes herein referred to as a peptide fragment containing a CTL epitope.
  • the peptide fragment may be a fragment of the native protein or an analogue or derivative thereof, provided that such peptide fragment is recognized by CTL induced by the native protein or CTL epitope of such native protein.
  • the peptide fragment may be comprised of only the amino acid residues which form the CTL epitope, or it may include additional amino acid residues; however, as hereinabove noted, the fragment contains less amino acid residues than the native protein.
  • a peptide fragment which includes an epitope which is recognized by CTL induced by the NEF protein of HIV-1 (hereinafter sometimes referred to as NEF protein) .
  • the peptide fragment which includes a CTL epitope which is recognized by CTL induced by NEF protein may be a fragment of the NEF protein containing such a CTL epitope or an analogue or derivative thereof.
  • the CTL epitope of the NEF protein is contained in amino acid residues 73 to 97 of NEF protein according to the Los Alamos, National Laboratory HIV sequence data base as follows (single letter amino acid code)
  • a peptide fragment which includes an epitope which is recognized by CTL induced by the GAG protein of HIV-1 or CTL epitope thereof (sometimes hereinafter referred to as GAG protein) .
  • the peptide fragment which includes a CTL epitope which is recognized by CTL induced by GAG protein may be a fragment of the GAG protein containing such a CTL epitope or an analogue or derivative thereof.
  • the CTL epitope of the GAG protein is contained in amino acid residues 179 to 193 of the GAG protein, which has the following structure as defined by the single letter amino acid code:
  • a peptide fragment which includes an epitope which is recognized by CTL induced by the ENV protein of HIV-1 or CTL epitope thereof (sometimes hereinafter referred to as ENV protein) .
  • the peptide fragment which includes a CTL epitope which is recognized by CTL induced by ENV protein may be a fragment of the ENV protein containing such a CTL epitope or an analogue or derivative thereof.
  • the CTL epitope of the ENV protein is contained in amino acid residues 566 to 590 of the ENV protein, which has the following structure as defined by the single letter amino acid code:
  • a peptide fragment which includes another epitope which is recognized by CTL induced by the ENV protein of HIV-1 or a CTL epitope thereof.
  • This CTL epitope of the ENV protein is contained in amino acid residues 54 to 80 of the ENV protein, which has the following structure as defined by the letter amino acide code:
  • CAS D or E, preferably D)A(K or R, preferably K)(A or S, preferably A)Y(D,S,K, or E, preferably D)(T,K, or P, preferably T)E(V,A,S, or K, preferably V)HN(V or I, preferably V)WA(T or K, preferably T)(H or Q, preferably H)ACVP(T or S, preferably T)(D or N, preferably D)P(N or S, preferably N).
  • the peptides hereinabove described may be produced by known techniques and obtained in substantially pure form.
  • the peptides may be synthesized on an automatic synthesizer. Journal of the American Chemical Society, Vol. 85, pages 2149-54 (1963). It is also possible to produce such peptides by genetic engineering techniques.
  • the peptide may also be produced by chemical or enzymatic buildup from smaller peptide fragments , or by cleavage of larger peptides or proteins or by solution phase peptide synthesis.
  • a peptide fragment which includes an epitope, which is recognized by CTL induced by an HIV protein may be employed in an assay for determining HIV infection. More particularly, the assay comprises contacting cells coated with a peptide fragment including a CTL epitope, which is recognized by CTL induced by a HIV protein, with lymphocytes from the animal, and determining lysis of the cells to indicate infection of the animal with HIV.
  • the cells coated with peptide are either autologous cells or an in vitro cell line compatible with the HLA type (MHC allele(s)) of the animal being tested.
  • the peptide fragment containing a CTL epitope may be a peptide fragment of the NEF protein, or a peptide fragment of the GAG protein, or a peptide fragment of the ENV protein or analogs or derivatives thereof as hereinabove described, or mixtures thereof.
  • an assay is effective for testing an individual of a particular HLA type for CMI responses to said peptide fragments .
  • B-cells from the animal are coated with a peptide fragment having a CTL epitope of an HIV protein as hereinabove described.
  • the B-cells may include a detectable label or marker, such as a radioactive chromium marker.
  • the B-cells are then contacted with peripheral blood lymphocytes (or PBL) from the animal. If the peripheral blood lymphocytes contain CTL induced by an HIV protein containing the CTL epitope of the peptide fragment , the CTL will recognize the CTL epitope of the peptide fragment coating the B-cells, and will lyse the B-cells. Lysis of the B-cells will be indicated by release of the detectable marker into the assay medium.
  • a process for augmenting a CTL response which comprises contacting peripheral blood lymphocytes from an animal infected with HIV with a peptide fragment(s) including a CTL epitope as hereinabove described.
  • the peptide fragment preferably contains a CTL epitope of the NEF protein, or a CTL epitope of the GAG protein, or a CTL epitope of the ENV protein.
  • the CTL response may be induced in vitro.
  • the CTL response may be augmented in vitro by incubating peripheral blood mononuclear cells (PBMC's) from seropositive individuals with a peptide of the type hereinabove described.
  • PBMC's peripheral blood mononuclear cells
  • peripheral blood lymphocytes having augmented CTL may then be used to treat the animal.
  • PBL augmented in CTL may be administered intravenously as an appropriate physiological suspension (for example in PBS) containing from 10 to 10 10 cells.
  • CTL may be induced in vivo by administering to an animal infected with HIV a peptide fragment having a CTL epitope of the type hereinabove described. More particularly, CTL will be induced in vivo by immunization with constructs that contain CTL sites against HIV that have been described above (E.g. Nef7). These vaccines can be formulated using standard techniques with carriers and/or adjuvants (for example, alum, bacterial cell wall components, vegetable oil formulations or derivatives thereof, etc.) to induce CTL responses.
  • carriers and/or adjuvants for example, alum, bacterial cell wall components, vegetable oil formulations or derivatives thereof, etc.
  • a peptide or peptide derivative having a CTL epitope can be synthesized and/or chemically modified to contain exogenous amino acids and/or fatty acid or hydrophobic moieties necessary for induction and/or augmentation of a CTL response.
  • An example of a method of modifying a peptide or peptide derivative having a CTL epitope is described in Deres , et al, Nature, Vol. 342, November 30, 1989, pgs . 561-564.
  • the dosage and administration protocol can be optimized in accordance with standard vaccination practices. A useful dosage for an average adult can be in the range of 1.0 to 1500 micrograms.
  • EXAMPLE I (a) Recombinant vaccinia virus construction.
  • the nef coding sequence was obtained from Dr. Venkatesan, Laboratory of Medical Microbiology, NIAID, NIH, as a cDNA clone.
  • the cDNA was derived from the HIV isolate, NL432 (Adachl et a. (1986) J. Virol. 59, 284).
  • the nef gene was excised and placed into a vaccinia virus integration vector.
  • the integration vector contains a vaccinia virus promoter termed P 7.5. Promoter P 7.5 allows expression of foreign genes at early and late times after infection.
  • the nef coding sequence was placed downstream of p 7.5.
  • the P 7.5 nef casette was inserted into the thymidine kinase (TK) locus of vaccinia virus by standard procedures resulting in insertional inactivation of TK.
  • TK thymidine kinase
  • a TK-recombinant vaccinia virus, designated vTFnef was isolated and purified. Expression studies were performed with vTFnef to confirm proper expression of Nef. Cell monolayers were infected with vTFnef in the presence of radiolabeled amino acids or myristic acid. Cell lysates were immunoprecipitated with Nef anti-serum. A specific 27 kd protein was precipitated. The 27 kd protein corresponds to the predicted molecular size as well as previously reported values for Nef (J.S.
  • Nef is also myristoylated demonstrating authentic expression of the nef coding sequence.
  • Autologous cells were prepared from B lymphocytes obtained from the same patient tested for CTL activity, i.e. to match HLA types for both target and effector cells .
  • Autologous B lymphoblastoid cell lines from these HIV seropositive patients were prepared by transformation wtih f Epstein-Barr Virus (EBV) as described previously (Blumberg et al. (1987) J. Infect. Dis. 155, 877; Koenig et al. (1988) Proc. Natl. Acad. Sci USA 85, 8638-8642). These cell lines were used as targets in an autologous chromium-release assay as described by Koenig, et al. (ibid).
  • EBV Epstein-Barr Virus
  • lysis of labeled target cells results in the release of chromium into the medium.
  • Freshly isolated autologous PBMC were used as effector cells in the assay. Two subjects had a Nef-specific cytotoxic response that was approximately five-fold higher than that observed for control vaccinia virus infected target cells.
  • Nef7 This peptide, designated Nef7, corresponds to Nef amino acid residues 73 to 97 according to the Los Alamos National Laboratory HIV sequence database. The N- and C-terminal boundaries of this epitope were fine-mapped by peptide deletions (A summary of peptides used for fine-mapping is shown in Table 1). A 10 residue peptide (10-mer), Nef7B, corresponding to residues 73 to 82 (QVPLRPMTYK) , was capable of serving as the CTL epitope with the same reactivity as Nef7 (25-mer).
  • Peptide NEf7B is contained within a highly conserved region of the Nef protein sequence (at least 90 percent conserved in all HIV-1 isolates sequenced to date). Although these subjects were classified as seropositive by standard screening assays; detection of antibody responses to Nef was negative by radioimmunoassay.
  • PAM insoluble copolymer
  • the symmetric anhydride derivatives were used as the acylating species for all amino acids except asparagine, glutamine, arginine and histidine. These four amino acids were coupled as the 1-hydroxybenzotriazole esters. The reactive side chains of amino acids were protected during the synthesis.
  • the protecting groups used were 0-benzyl for Asp and Glu; benzyl for Ser and Thr; p-methylbenzyl group for Cys; tosyl for Arg; dinitrophenyl for His; 2-chlorobenzyloxycarbonyl for Lys; 2-bromobenzyloxycarbonyl for Tyr; and formyl for Trp.
  • peptides were cleaved with anhydrous liquid HF in the presence of anisole, dimethlysulfide and ethanedithiol. Once cleaved the peptides were precipitated in ether, and then extracted from the resin with 30% (v/v)glacial acetic acid in water.
  • the cleaved peptides from the resin were analyzed and subsequently purified to greater than 95% homogeneity, using a Vydac C-4 reverse-phase column, and Beckman "System Gold” HPLC.
  • the correct amino acid content of each peptide was verified by hydrolyzing purified material with constant boiling in 6N HC1 at 150 degrees centigrade for 2 hours . Once hydrolyzed, these samples were then subject to amino acid compositional analysis using the Beckman "System Gold” amino acid analyzer. (e) CTL assay.
  • PBMCs Preparation of PBMCs , generation of autologous lymphoblastoid cell lines and cytotoxicity microassays (CTL) were done as described in part (b) above except that the autologous B lymphoblastoid cell line was coated with the Nef7 peptide instead of being infected with the noted viral vector.
  • CTL cytotoxicity microassays
  • animal as used herein includes humans and non-humans and is preferably a human. It is to be understood, however, that the scope of the present invention is not to be limited to the specific embodiments described above. The invention may be practiced other than as particularly described, and within the scope of the accompanying claims, numerous modifications may be made of the specific teachings contained herein.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Fragments de peptide de protéines HIV telles que la protéine NEF, la protéine GAG et la protéine ENV, comprenant un épitope CTL. De tels fragments de peptide contenant des épitopes CTL peuvent être utilisés pour induire ou augmenter les réponses d'immunité cellulaire contre le virus HIV pour traiter ou prévenir l'infection de l'animal par le virus HIV.
EP19900914632 1989-09-19 1990-09-19 Peptides including ctl epitopes of hiv proteins and use thereof Withdrawn EP0491844A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40959689A 1989-09-19 1989-09-19
US409596 1995-03-24

Publications (2)

Publication Number Publication Date
EP0491844A1 true EP0491844A1 (fr) 1992-07-01
EP0491844A4 EP0491844A4 (en) 1993-02-17

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EP19900914632 Withdrawn EP0491844A4 (en) 1989-09-19 1990-09-19 Peptides including ctl epitopes of hiv proteins and use thereof

Country Status (4)

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EP (1) EP0491844A4 (fr)
JP (1) JPH05502442A (fr)
CA (1) CA2025634A1 (fr)
WO (1) WO1991004051A1 (fr)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8429099D0 (en) 1984-11-16 1984-12-27 Pasteur Institut Closed dna sequences
US7232654B1 (en) 1983-09-15 2007-06-19 Institut Pasteur DNA sequence of the LTR region of human immunodeficiency virus type 1 (HIV-1)
GB8423659D0 (en) 1984-09-19 1984-10-24 Pasteur Institut Cloned dna sequences
US7205102B1 (en) 1983-09-15 2007-04-17 Institut Pasteur Cloned DNA sequences related to the genomic RNA of lymphadenopathy-associated virus (LAV) and proteins encoded by said LAV genomic RNA
US5980900A (en) * 1984-10-18 1999-11-09 Institut Pasteur And Centre National De La Recherche Scientifique Amino acid DNA sequences related to genomic RNA of human immunodeficiency virus (HIV-1)
US5705612A (en) 1984-10-18 1998-01-06 Institut Pasteur And Centre National De La Recherche Scientifique NEF peptide encoded by human immunodefiency virus type 1 (HIV-1)
US7045130B1 (en) 1984-10-18 2006-05-16 Institut Pasteur Antibodies against antigens of human immunodeficiency virus (HIV-1)
US6894152B1 (en) 1984-11-16 2005-05-17 Institut Pasteur Cloned DNA sequences related to the genomic RNA of lymphadenopathy-associated-virus (LAV) and proteins encoded by said LAV genomic RNA
US6210873B1 (en) 1987-08-28 2001-04-03 Board Of Regents, The University Of Texas System Methods and compositions for the priming of specific cytotoxic T-lymphocyte response
US5128319A (en) 1987-08-28 1992-07-07 Board Of Regents, The University Of Texas System Prophylaxis and therapy of acquired immunodeficiency syndrome
US5993819A (en) * 1987-09-08 1999-11-30 Duke University Synthetic vaccine for protection against human immunodeficiency virus infection
US5221610A (en) * 1988-05-26 1993-06-22 Institut Pasteur Diagnostic method and composition for early detection of HIV infection
EP0521220A1 (fr) * 1991-06-14 1993-01-07 Institut Pasteur Actinomycétale immunogène recombinant
EP0968721A3 (fr) * 1991-12-02 2004-02-04 The Board Of Regents, The University Of Texas System Utilisation d'une composition peptidique pour l'inhibition du HIV
WO1993019775A1 (fr) * 1992-03-31 1993-10-14 Medimmune, Inc. Administration de liposomes contenant des peptides ou des proteines comportant des determinants antigeniques de ctl de proteines vih
US5603933A (en) * 1993-08-31 1997-02-18 Board Of Regents, The University Of Texas CD4 peptides for binding to viral envelope proteins
DE4405810A1 (de) 1994-02-23 1995-08-24 Behringwerke Ag Von einem Retrovirus aus der HIV-Gruppe abgeleitete Peptide und deren Verwendung
CN1327896C (zh) * 1996-10-10 2007-07-25 探针国际公司 治疗病毒感染的组合物及方法
DK1240186T3 (da) 1999-12-23 2010-05-31 Medical Res Council Forbedringer i eller relateret til immunrespons mod HIV
IL150961A0 (en) 2000-02-04 2003-02-12 Univ Duke Human immunodeficiency virus vaccine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0273716A2 (fr) * 1986-12-30 1988-07-06 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce Peptides synthétiques induisant l'immunité cellulaire contre le virus du SIDA et ses protéines
WO1989002277A2 (fr) * 1987-08-28 1989-03-23 Board Of Regents, The University Of Texas System Prophylaxie et therapie du syndrome immunodeficitaire acquis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0273716A2 (fr) * 1986-12-30 1988-07-06 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce Peptides synthétiques induisant l'immunité cellulaire contre le virus du SIDA et ses protéines
WO1989002277A2 (fr) * 1987-08-28 1989-03-23 Board Of Regents, The University Of Texas System Prophylaxie et therapie du syndrome immunodeficitaire acquis

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BIOTECHNOLOGY vol. 3, October 1985, NEW YORK US pages 905 - 909 TSE WEN CHANG ET AL. 'Detection of antibodies to human T-cell lymphotropic virus-III (HTLV-III) with an immunoassay employing a recombinant Escherichia coli-derived viral antigenic peptide' *
NATURE vol. 336, no. 6198, 1 December 1988, LONDON GB pages 484 - 487 DOUGLAS F. NIXON ET AL. 'HIV-1 gag-specific cytotoxic T lymphocites defined with recombinant vaccinia virus and synthetic peptides' *
See also references of WO9104051A1 *

Also Published As

Publication number Publication date
JPH05502442A (ja) 1993-04-28
WO1991004051A1 (fr) 1991-04-04
EP0491844A4 (en) 1993-02-17
CA2025634A1 (fr) 1991-03-20

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