WO1994017825A1 - Mutants de genes multiples du virus d'immunodeficience humaine utilises dans un vaccin - Google Patents

Mutants de genes multiples du virus d'immunodeficience humaine utilises dans un vaccin Download PDF

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Publication number
WO1994017825A1
WO1994017825A1 PCT/US1993/012088 US9312088W WO9417825A1 WO 1994017825 A1 WO1994017825 A1 WO 1994017825A1 US 9312088 W US9312088 W US 9312088W WO 9417825 A1 WO9417825 A1 WO 9417825A1
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Prior art keywords
plasmid
human immunodeficiency
deletions
immunodeficiency virus
nef
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PCT/US1993/012088
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English (en)
Inventor
David J. Looney
Flossie Wong-Staal
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The Regents Of The University Of California
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Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Priority to AU58487/94A priority Critical patent/AU5848794A/en
Publication of WO1994017825A1 publication Critical patent/WO1994017825A1/fr

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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
    • 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
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • 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
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15022—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
    • C12N2740/16061—Methods of inactivation or attenuation
    • 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
    • C12N2740/16311—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

  • the invention herein relates to live-virus vaccines and their production and use.
  • Live virus vaccines possess many desirable properties. Perhaps the most successful vaccines of any kind are those which employ live attenuated virus to elicit effective and extremely long lasting immunity in a very high proportion of immunized subjects. Live virus vaccines often induce effective immunity with a single immunization, making them ideal vaccines for large-scale use in developing countries, While killed virus vaccines can be effective, even against lethal agents, immunity is often short lived, such that multiple immunizations can be required even for transient protection.
  • SIV simian immunodeficiency virus
  • a more immediate application of attenuated virus vaccines may include their use as immunotherapeutic agents in the treatment of HIV infected individuals.
  • a number of therapeutic vaccines are in clinical trial, including the use of inactivated envelope-deficient virus and the use of recombinant envelope protein.
  • retrovirus vectored expression of HIV envelope protein is being developed as a therapeutic vaccine. The persistence, potency, and breadth of the immune responses elicited by these vaccines would be limited compared to that expected for a live attenuated virus vaccine.
  • the invention herein of safe and immunogenic molecular clones (mutants) of HIV-1 which have been altered to exhibit minimal cytopathogenicity, impaired and/or limited infectivity, and susceptibility to complete eradication by various non-toxic agents.
  • mutants of HIV-1 possess multiple genetic defects, including defects in the vif, vpu , env, vpr, and nef genes.
  • Cell lines for production of several of these viruses (Molt-3/X295 ⁇ S135, Molt3/X295 ⁇ S) have also been double-cloned by limiting dilution and repeated screening.
  • HXB2gpt phenotypically vpr- , vpu- , nef-
  • HXB2 ⁇ S containing a large deletion in vif and vpr
  • X295 containing a deletion of the carboxy-terminal envelope and nef regions in the HXB2 background
  • HXB2ala313 constructed fro HXB2, containing an envelope cassette from BH10 with a two-base mutation changing the "gpgr" motif at the tip of the V3 loop in env to "gagr"
  • HXB2 ⁇ 135 containing a 84 bp deletion of the V3 loop in env, again in a HXB2 background containing the BH10
  • the invention herein includes a method for the production of attenuated human immunodeficiency viruses (HIV) which comprises providing a plasmid comprising a proviral HIV clone and env , nef, vif, and vpr regions, and deleting from the plasmid significant portions of at least three of the env, nef, vif, and vpr regions, whereby the plasmid following deletion exhibits cell-free infectivity and reduced syncytium formation ability.
  • HIV human immunodeficiency viruses
  • the initial plasmid is pHXB2gpt or a mutant thereof having deletions in not more than two of the env , nef, vif, and vpr regions.
  • the plasmid will also contain an int or tat region with a deletion therein.
  • a plasmid comprising a proviral HIV clone and env, nef, vif, and vpr regions, from which significant portions of initial lengths of at least three of the env, nef, vif, and vpr regions have been deleted, the resultant product plasmid with the deletions exhibiting cell-free infectivity and reduced syncytium formation ability.
  • deletions are made in all four of said regions.
  • the initial plasmid is pHXB2gpt or a mutant thereof having deletions in not more than two of the env, nef, vif, and vpr regions.
  • the plasmid will also contain an int or tat region with a deletion therein.
  • One may also include a polylinker for subcloning of at least one suicide gene.
  • an attenuated human immunodeficiency virus comprising a plasmid comprising a proviral HIV clone and env, nef, vif, and vpr regions, from which significant portions of initial lengths of at least three of the env, nef, vif, and vpr regions have been deleted, the resulting plasmid with said deletions exhibiting cell- free infectivity and reduced syncytium formation ability.
  • deletions are made in all four of said regions.
  • the initial plasmid is pHXB2gpt or a mutant thereof having deletions in not more than two of the env, nef, vif, and vpr regions.
  • the plasmid will also contain an int or tat region with a deletion therein.
  • the invention also includes a method for prophylactic prevention of infection of a person by a human immunodeficiency virus which comprises administering to the person a prophylactically effective amount of the attenuated human immunodeficiency virus of this invention; a vaccine for such prophylactic prevention of infection; a method for therapeutic treatment of infection of a person infected by a human immunodeficiency virus which comprises administering to said person a therapeutically effective amount of the attenuated human immunodeficiency virus of this invention; and a vaccine for therapeutic treatment (including amelioration or possible cure) of a person infected by a human immunodeficiency virus which comprises a therapeutically effective amount of the attenuated human immunodeficiency virus of this invention.
  • Vectored delivery is contemplated by the plasmid of this invention having an envelope devoid of promoter and polyadenylation signal regions; providing a method of vectored prophylactic prevention of infection of a person by a human immunodeficiency virus which comprises administering to said person a prophylactically effective amount of that plasmid encompassed in a replication- deficient virus; and providing a method of vectored therapeutic treatment of a person infected by a human immunodeficiency virus which comprises administering to said person a therapeutically effective amount of that plasmid encompassed in a replication-deficient virus.
  • Figure 1 is a schematic diagram of one of the starting materials, the HXB2gpt proviral plasmid, showing the location of various restriction sites.
  • Figure 2 is a schematic diagram of various multiple gene mutants of the present invention, showing the various regions and indicating where deletions occur.
  • Figure 3 is a graph showing reduced syncytia production by attenuated mutants adjusted for efficiency of transfection [1 ⁇ g proviral DNA, HT4-LacZ (Magi-Emmerman) cells] .
  • Figure 4 is a graph comparable gag p24 production by attenuated mutants adjusted for efficiency of transfection.
  • Figure 5 is a graph showing reduced killing by the ala313 mutant as compared to that of HXB2 (both at 100xTCID 50 ], and including infectivity, cytopathogenicity and syncytia production.
  • Figure 6 is a graph showing the restoration of cell- free infectivity in the X295 ⁇ S-v/ mutant, with self- reinfectivity of frech human leukocytes as (SFU/ml-HT48C, TCID-PBMC) per -1000 pg p24.
  • the invention herein encompasses several different forms of the HIV-1 virus mutants.
  • attenuated live viruses i.e., viruses impaired in infectivity, cytopathogenicity, or actual pathogenicity which are capable of indefinite replication in the host, at some level
  • attenuated live viruses with suicide genes i.e., viruses expressing genes which are normally harmless to the host but which can trigger cell death in the presence of pharmacologic agents (e.g.
  • thymidine kinase and ganciclovir allowing the populations of infected cells in the immunized host to be eradicated; controlled attenuated viruses, i.e., totally replication defective viruses which require addition of essential viral proteins as exogenous agents (e.g. TAT protein) in order to replicate In the host; and vectored or complemented replication defective viruses, i.e., viruses which will undergo only a single round or two rounds of replication which result in production of infectious virions due to complementation in producer lines or initial target cells, but which subsequently produce only non-infectious virions.
  • controlled attenuated viruses i.e., totally replication defective viruses which require addition of essential viral proteins as exogenous agents (e.g. TAT protein) in order to replicate In the host
  • vectored or complemented replication defective viruses i.e., viruses which will undergo only a single round or two rounds of replication which result in production of infectious virions due to complementation in producer lines or initial target cells, but which subsequently produce only
  • the starting clones included HXB2gpt (phenotypically vpr- , vpu- , nef-) , HXB2 ⁇ S (containing a large deletion in vif and vpr, X295 (containing a deletion of the carboxy-terminal envelope and nef regions in the HXB2 background) , HXB2ala313 (constructed from HXB2, containing an envelope cassette from BH10 with a two-base mutation changing the "gpgr" motif at the tip of the V3 loop to "gagr") , and HXB2 ⁇ 135 containing a 84 bp deletion of the V3 loop, again in a HXB2 background containing the BH10 envelope cassette) .
  • Mutant viruses created included HXB2 ⁇ Sala313, HXB2 ⁇ S ⁇ 135, X95 ⁇ S, X295ala313, X295 ⁇ 135, X295 ⁇ Sala313, and X295 ⁇ S ⁇ 135 (some of which are shown in Figure 2) .
  • plasmids provide a convenient SstI plasmid fragment, devoid of promoter and polyadenylation signal, which can be moved into other expression cassettes.
  • replication-deficient DNA viruses CMV, HSV and BPV vectors
  • this is believed to be capable of providing all of the advantages of live-virus vaccines (complete particle production, intracellular production of proteins, persistent presentation for several weeks to months) in the context of a proviral clone which is totally incapable of producing infections particles due to the deletion in the 3'-LTR (required for successful reverse-transcription and integration.)
  • the invention also encompasses clones with deletions of additional genes, including clones with deletions in the first coding exon of tat and an int mutant which would be limited to a single round of infection, with subsequent production of intact yet non-infectious virus particles. These are constructed in the background of the X295 ⁇ S and X295 ⁇ Sala313 clones. Such additional mutations may also be moved into the LTR-deleted X194 based clones. TAT defective mutants may be created by PCR mutagenesis, with introduction of three stop codons into the tat first exon, to complement with recombinant TAT protein.
  • integrase mutants and complementary producing lines may be achieved by inserting multiple frame stop cloning sites at the beginning of int by PCR mutagenesis, and deleting int and remaining vpr (whole central region of the virus) to just before the tat splice acceptor (Sail site) , while amplifying int with other primer pairs (with introduction of a consensus start signal, acylation signal, and protease cleavage signal) for cloning into a CMV promoter plasmid.
  • Plasmids such as pMAMneo, pRc/RSV, pRe/CMV and pcDNAIneo each have some distinct advantages and liabilities, but those skilled in the art will be easily able to select appropriate vectors in different situations for expression in trans, leaving no shared sequences with the proviral plasmid.
  • the vif-vpr deletion in native X295 may be reconstructed, using a unique Xcml-Ncol sites, to insert a polylinker for subcloning of one or two suicide genes,such as HSV tk and bacterial xgpt genes, into the viral vif and nef reading frames.
  • suicide genes such as HSV tk and bacterial xgpt genes
  • Both of these genes allow both positive and negative selection using certain cell lines and agents in vitro , allowing easy selection of producing clones using mycophenolic acid/HAT selection, etc. Negative selection is included to permit in vivo eradication of expressing clones.
  • HIV-1 HN and wild-type strain envelopes may be amplified for this purpose. This should alleviate any expectation that since HXB2 (from III B /LAV/LAI) is not a prevalent strain, it would not be particularly appropriate for vaccine purposes, especially with respect to envelope coding sequences.
  • Characterization of clones in vitro is by a variety of means, including confirmation of expected patterns of protein expression; replication in primary cells, such as CD4+ lymphocytes and monocytes; replication in cell lines; syncytium forming capability in vitro ; cell killing in vitro ; and demonstration of eradication of clones containing suicide genes by selective agents in vitro .
  • Selection and characterization of producing lines and virus preparations for inoculation must adhere to good manufacturing practices standard for animal and human administration.
  • the various mutants may be tested in animal models in a number of different types of experiments, including but not limited to establishment of infectivity in macaque cells; infectivity for M. nomestrina; exploration of cutaneous inoculation; evaluation of proviral persistence; evaluation of immunogenicity, including neutralizing antibody, ADCC, and cytolytic activity; and eradication of clones containing suicide genes.
  • the route of administration in humans is expected to be by cutaneous (intradermal) or subcutaneous administration. Both single and multiple injections are contemplated.

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Abstract

L'invention décrit un procédé de production de virus d'immunodéficience humaine atténués. Ce procédé comprend la production d'un plasmide ayant un génome HIV proviral comprenant les gènes env, nef, vif et vpr, et la délétion, de portions significatives du plasmide, d'au moins trois gènes, et de préférence des quatre gènes, de sorte que le plasmide obtenu code un virus atténué qui présente un infectivité non cellulaire et une capacité de formation de syncytium réduite. L'invention décrit également un procédé de prévention prophylactique d'infection d'une personne par le virus HIV, ce procédé consistant à lui administrer une quantité ayant une efficacité prophylactique du virus atténué, un vaccin pour une telle prévention prophylactique, un procédé de traitement thérapeutique comprenant l'administration d'une quantité thérapeutiquement efficace du virus atténué et un vaccin pour un traitement thérapeutique.
PCT/US1993/012088 1993-02-05 1993-12-13 Mutants de genes multiples du virus d'immunodeficience humaine utilises dans un vaccin WO1994017825A1 (fr)

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AU58487/94A AU5848794A (en) 1993-02-05 1993-12-13 Multiple-gene mutants of human immunodeficiency virus (hiv) for vaccine use

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US1431893A 1993-02-05 1993-02-05
US08/014,318 1993-02-05

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995021912A1 (fr) * 1994-02-14 1995-08-17 The Macfarlane Burnet Centre For Medical Research Limited Souches non pathogenes de vih-1
WO1997032983A1 (fr) * 1996-03-05 1997-09-12 The Regents Of The University Of California Virus de l'immunodeficience feline vivants recombines et vaccins d'adn proviraux
US6001985A (en) * 1995-04-14 1999-12-14 University Of Alabama Research Foundation Fusion protein delivery systems and uses thereof
US6015661A (en) * 1994-02-14 2000-01-18 The Macfarlane Burnet Centre For Medical Research Limited Methods for the detection of non-pathogenic HIV-1 strains containing deletions in the Nef coding region and U3 region of the LTR
WO2000009703A1 (fr) * 1998-08-12 2000-02-24 University Of Western Ontario Vaccin contre le virus de l'immunodeficience humaine (vih)
WO2002020571A2 (fr) * 2000-09-08 2002-03-14 Biomerieux B.V.A. Souches vih attenuees et leur utilisation
US6555342B1 (en) 1998-06-03 2003-04-29 Uab Research Foundation Fusion protein delivery system and uses thereof
EP1283272A3 (fr) * 2001-08-08 2004-02-25 Tibotec Pharmaceuticals Ltd. Méthodes et moyens d'évaluation d'une thérapie à base des inhibiteurs de l'enveloppe du VIH
US6713286B2 (en) * 1998-08-24 2004-03-30 Pfizer Inc. Compositions and methods for protecting animals from lentivirus-associated disease such as feline immunodeficiency virus
US7067134B1 (en) 1998-08-12 2006-06-27 University Of Western Ontario HIV vaccine
US7608273B2 (en) 1998-08-12 2009-10-27 University Of Western Ontario Recombinant lentivirus encoding modified GP 120 signal sequences
US7622300B2 (en) 1998-06-03 2009-11-24 Kappes John C Trans-lentiviral vector particles and transduction of eukaryotic cells therewith

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2186398A1 (fr) * 1994-03-25 1995-10-05 Ahmed A. Azad Proteines vpr et vpx du vih

Citations (1)

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WO1992000987A1 (fr) * 1990-07-12 1992-01-23 President And Fellows Of Harvard College Vaccins prepares a partir d'un lentivirus de primate

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WO1992000987A1 (fr) * 1990-07-12 1992-01-23 President And Fellows Of Harvard College Vaccins prepares a partir d'un lentivirus de primate

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Title
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AIDS RESEARCH AND HUMAN RETROVIRUSES, Volume 8, Number 3, issued March 1992, R.C. DESROSIERS, "HIV with Multiple Gene Deletions as a Live Attenuated Vaccine for AIDS", pages 411-421. *
AIDS RESEARCH AND HUMAN RETROVIRUSES, Volume 8, Number 8, issued August 1992, R.C. DESROSIERS, "HIV with Multiple Gene Deletions as a Live Attenuated Vaccine for AIDS", page 1457. *
IMMUNOBIOLOGY, Volume 184, Number 2/3, issued February 1992, S. NORLEY et al., "Vaccination Against HIV", pages 193-207. *
JOURNAL OF VIROLOGY, Volume 65, Number 11, issued November 1991, D. DEDERA et al., "Demonstration of Two Distinct Cytopathic Effects with Syncytium Formation-Defective Human Immunodeficiency Virus Type 1 Mutants", pages 6129-6136. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA, Volume 87, issued October 1990, N. HATTORI et al., "The Human Immunodeficiency Virus Type 2 vpr Gene is Essential for Productive Infection of Human Macrophages", pages 8080-8084. *
SCIENCE, Volume 258, issued 18 December 1992, M.D. DANIEL et al., "Protective Effects of a Live Attenuated SIV Vaccine with a Deletion in the nef Gene", pages 1938-1941. *
THE NEW BIOLOGIST, Volume 3, Number 7, issue July 1991, G. PLAUTZ et al., "Selective Elimination of Recombinant Genes In Vivo with a Suicide Retroviral Vector", pages 709-715. *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995021912A1 (fr) * 1994-02-14 1995-08-17 The Macfarlane Burnet Centre For Medical Research Limited Souches non pathogenes de vih-1
US6015661A (en) * 1994-02-14 2000-01-18 The Macfarlane Burnet Centre For Medical Research Limited Methods for the detection of non-pathogenic HIV-1 strains containing deletions in the Nef coding region and U3 region of the LTR
US6001985A (en) * 1995-04-14 1999-12-14 University Of Alabama Research Foundation Fusion protein delivery systems and uses thereof
US7534603B2 (en) 1995-04-14 2009-05-19 The Uab Research Foundation Fusion protein delivery system and uses thereof
US6362000B1 (en) 1995-04-14 2002-03-26 University Of Alabama Research Foundation Fusion protein delivery system and uses thereof
WO1997032983A1 (fr) * 1996-03-05 1997-09-12 The Regents Of The University Of California Virus de l'immunodeficience feline vivants recombines et vaccins d'adn proviraux
US6004799A (en) * 1996-03-05 1999-12-21 The Regents Of The University Of California Recombinant live feline immunodeficiency virus and proviral DNA vaccines
US7622300B2 (en) 1998-06-03 2009-11-24 Kappes John C Trans-lentiviral vector particles and transduction of eukaryotic cells therewith
US7259014B2 (en) 1998-06-03 2007-08-21 Uab Research Foundation Fusion protein delivery system and uses thereof
US6555342B1 (en) 1998-06-03 2003-04-29 Uab Research Foundation Fusion protein delivery system and uses thereof
US7067134B1 (en) 1998-08-12 2006-06-27 University Of Western Ontario HIV vaccine
US7608273B2 (en) 1998-08-12 2009-10-27 University Of Western Ontario Recombinant lentivirus encoding modified GP 120 signal sequences
WO2000009703A1 (fr) * 1998-08-12 2000-02-24 University Of Western Ontario Vaccin contre le virus de l'immunodeficience humaine (vih)
US6713286B2 (en) * 1998-08-24 2004-03-30 Pfizer Inc. Compositions and methods for protecting animals from lentivirus-associated disease such as feline immunodeficiency virus
WO2002020571A3 (fr) * 2000-09-08 2003-03-13 Biomerieux B V A Souches vih attenuees et leur utilisation
WO2002020571A2 (fr) * 2000-09-08 2002-03-14 Biomerieux B.V.A. Souches vih attenuees et leur utilisation
EP1283272A3 (fr) * 2001-08-08 2004-02-25 Tibotec Pharmaceuticals Ltd. Méthodes et moyens d'évaluation d'une thérapie à base des inhibiteurs de l'enveloppe du VIH
US7306901B2 (en) 2001-08-08 2007-12-11 Tibotec Pharmaceuticals, Ltd. Methods and means for assessing HIV envelope inhibitor therapy

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