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WO1992022572A1 - Nouveaux peptides gag et env du vih-1, diagnostic - Google Patents

Nouveaux peptides gag et env du vih-1, diagnostic Download PDF

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Publication number
WO1992022572A1
WO1992022572A1 PCT/SE1992/000423 SE9200423W WO9222572A1 WO 1992022572 A1 WO1992022572 A1 WO 1992022572A1 SE 9200423 W SE9200423 W SE 9200423W WO 9222572 A1 WO9222572 A1 WO 9222572A1
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WIPO (PCT)
Prior art keywords
hiv
peptides
african
env
strains
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Application number
PCT/SE1992/000423
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English (en)
Inventor
Jonas Blomberg
Rüdiger Pipkorn
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Replico Medical Ab
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Publication date
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Publication of WO1992022572A1 publication Critical patent/WO1992022572A1/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
    • 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

Definitions

  • the present invention relates to new peptides, to diagnostic antigens having the ability to specifically bind antibodies raised against African HIV-1 strains, to the use of said diagnostic antigens in an immunoassay for discriminating between sera containing antibodies against
  • HIV-1 strains can differ by as much as 20% in their amino acid sequences compared to north American/European HIV-1 strains (2). The greatest sequence differences seen so far has been between some strains of Zairean and north American origin. Local East African
  • HIV-1 strains e.g. in Moscow and Kenya, differ as t well. r. HIV-1 seems to be spreading particularly rapidly in many African countries (3-6), predominantly through hete ⁇ rosexual contacts. Even the clinical picture of AIDS in
  • the main object of the present invention is to discriminate between sera originating from African HIV-1 infected individuals or individuals infected with diffe- rent African serotypes of HIV and non-African HIV-1 infec ⁇ ted individuals in a simple and exact test. This could provide a rapid, proper and exact treatment of possible AIDS-symptoms related to these types of HIV-1 strains, including immunization of already infected with an opti- mized combination of HIV-1 antigens.
  • a vaccine formulation based on the primary neutralization domain of gpl20 is derived from the pep ⁇ tides of the invention. The above mentioned objects are satisfied by the pre ⁇ sent invention.
  • the present invention relates to pepti ⁇ des with the formulas:
  • U is P or L, and U ' is Q or R, wherein Y in the peptides a ) -k ) is an optional amount of optional amino acids , but not so many that the function of the peptide is adversely affected, being preferably at most 3 optional amino acids ; or alternatively in the peptides g ) -k ) both Y are chemical bonds and the peptides are missing such an amount of amino acids that the total amount of present amino acids between said chemical bonds is at least 15; and wherein one X represents a chemical bond and the other X represents a chemical bond or a coupling facilitating amino acid sequence,and Z represents -NH memo or -OH.
  • the present invention relates to diagnostic antigens each containing one of the peptides above or antigeni ⁇ parts thereof, said diagnostic antigens having the ability to specifically bind antibodies raised against African HIV-1 strains, thus permitting discrimina ⁇ tion between sera containing antibodies against different African HIV-1 strains and also African versus non-African H V-1 strains.
  • the present invention relates to a method of discriminating between sera containing antibodies against different Africa HIV-1 strains and also African versus non-African HIV-1 strains, wherein at least one diagnostic antigen according to the present invention, optionally coupled to a carrier, is added to a positively diagnosed HIV-1 serum in an immunoassay, whereby the discrimininating is established based upon that if said diagnostic antigen(s) react selectively with the serum, the patient is infected with a certain African strain of HIV-1.
  • the present invention relates to a method wherein preferably a set of different diagnos ⁇ tic antigens according to claim 3 is added to said HIV-1 serum during the immunoassay, preferably antigens contain ⁇ ing the peptides a), e), f), i), j) and k).
  • a vaccine composition which as an immunizing component comprises at least one antigen according to the present invention together with a nontoxic pharmaceutically acceptable carrier and/or diluent.
  • the diagnostic antigen(s) is (are) inter alia useful for discrimination between sera containing antibodies raised against East African HIV-1 strains, e.g. cloudsan and Kenyan HIV-1 strains, and also African versus non- -African HIV-1 strains, but said diagnostic antigen(s) is (are) more or less generally useful as to all African HIV-1 strains, because of the structural similarity of HIV-1 strains in this part of the world.
  • Each of the peptides according to the present inven ⁇ tion reacts specifically as a diagnostic antigen with one of two sera, one of the sera containing antibodies raised against African HIV-1 strains and the other serum con ⁇ taining antibodies raised against non-African HIV-1 strains, for example European and North American HIV-1 strains.
  • the preferred peptides used in the diagnostic anti- gens according to the present invention are a), e), f), i), j ) and k).
  • a set of peptides is used in the immunoassay. The best results are obtained using as many of said pep ⁇ tides as possible. The optimal combination of peptides depends of course of the serum being analysed, but gene ⁇ rally the combination of the six preferred peptides above gives the best discrimination results.
  • the peptides according to the present invention are hitherto not known in the art and are synthetised with basis on either African HIV-1 strains or non-African HIV-1 strains.
  • the peptides according to the present invention are conveniently referred to as a) HIV-1 hxb2 gag 173-233 HIV-1 li env 487-508
  • the peptides g)-k) are related to the V3 neutralisa ⁇ tion loop of gpl20, and the peptides e) and f) to the C-terminal of gpl20.
  • HIV-1 the most common in the world
  • HIV-2 the partially structurally different HIV-2 is mainly restricted to West Africa.
  • the retro viruses HTLV-1 and HTLV-2 do not induce AIDS, but AIDS-related diseases, for example T-cell leu- kemia.
  • the present invention is therefore concerned with HIV-1 and amino acid sequences unique for the HIV-1 pro ⁇ teins are contemplated.
  • the interior parts, for example the nucleocapsid or the core containing the RNA, of the HIV-1 strains are pro- te ⁇ ted by an envelope.
  • env group-specific antigen
  • proteins i.e. the precursors, are predominant in the beginning of the virus life cycle, while others are predominant in later phases.
  • Amino acid sequences from the following viral strains were used.
  • z3, z321, jyl, eli and mal are Zairean HIV-1 strains isolated early in the epidemic, while mn and hxb2 are North American HIV-1 strains.
  • Table 1 lists major genes and gene products of HIV-1.
  • p55 is a precursor of p24 and/or pl7.
  • gpl60 is a precursor of gpl20 and gp41.
  • Y represents an optional amount of optional amino acids.
  • Y is 2 or 3 optional amino acids.
  • Y can represent more amino acids than so, but not so many that the function of the peptide is adver- sely affected.
  • both Y can be chemical bonds and said peptides are missing such an amount of amino acids that the total amount of amino acids present is at least 15.
  • the optionally missing amino acids above are of course located at the very end(s) of the peptides.
  • X represents a chemical bond or a sequence of at least 4, and preferably 8, particular amino acid residues, which each are chosen from the group consisting of -Thr- and -Ser-. When X is an amino acid sequence, it can be located either in the C- or N-terminus of the peptides but not in both ends at the same time.
  • X in the N-terminus corresponds to a chemical bond and vice versa.
  • X can be a bond at both ends of the peptide according to the present inven ⁇ tion.
  • Said amino acid sequence acts as a coupling facili ⁇ tating spacer, which permits proper binding to the carrier to which the peptides according to the present invention will be bound during the discrimination method.
  • the sequence X should not be an amino acid sequence which adversely affects the result of the diagnosis method. Accordingly, it should not have a too high charge or be too hydrophobic and it should not disturb the conformation of the peptides.
  • amino acids threonine and serine also fulfill these requirements particularly well, and any one of the amino acids in said sequence X can be threonine or serine.
  • the number of amino acids in this spacer sequence should be at least 4, but in a preferred embodiment accor ⁇ ding to the present invention 8 amino acids are used.
  • the polypeptides according to the present invention can be bound via the amino acid sequence X to a carrier by physical/chemical interaction, as for example covalent binding, ionic binding, hydrogen binding or hydrophobic binding. Examples of covalent binding are esther, ether and disulfide binding.
  • antigenic parts thereof relates to antigenic parts of the peptides according to the invention between the both Y in each peptide.
  • carrier used herein should be inter- preted broadly, and it can be any material which is compa- tible with and not negatively affects the method according to the present invention, for example resins, microplates, plastic surfaces, gels, matrixes etc.
  • epitopope used herein means antigenic or immunogenic determinant and relates to a specific part of a structure of an antigen inducing an immuno response, and the produced antibodies are directed against this part. Materials and methods Patients and sera
  • EIA enzyme immunoassay
  • the test kits were either Organon Vironostica HIV-1 (Organon biotechnika, Oss, The Netherlands) or Abbott Recombinant Screening EIA (Abbott laboratories, Chicago, IL, USA). Confirmation was made with electrophoretic immunoblot (EIB), in Harare, clouds, with the BioRad (Richmond, CA, USA), in Lund, Sweden, with the Biotech/DuPont (DuPont diagnostics, Billerica, NJ, USA) kits. Patients donating serum were, according to request forms, asymptomatic. Twenty HIV-1 positive sera originated from Harare, clouds, and twenty from southern Sweden.
  • HIV-1 antibody negative control sera were from twenty Swedish blood donors and from ten Zimbab ⁇ wean HIV-1 western blot negative sera. With some peptides only the Swedish control sera were tested. Unless indica ⁇ ted otherwise values from both control groups were presen ⁇ ted together. 26 HIV-1 seropositive sera, from a missio ⁇ nary hospital in Nkinga, Africa, were kindly provided by dr Bo-Erik Malmvall. Synthetic peptides
  • Zairean z321 HIV-1 strain was isolated from a serum taken in 1976, i.e. early in the HIV-1 pandemic (17).
  • jyl, eli, mal and z6 are also Zairean HIV-1 strains (2).
  • hxb2 is an infectious molecular clone of the north American HIV-1 strain HTLV III B. The following virus related abbreviations will be used hereinafter.
  • MA membrane anchoring protein (pl7)
  • CA capsid protein (p24)
  • NC nucleocapsid protein (p7).
  • Solid phase peptide synthesis was carried out in Heidelberg on an Applied Biosystems 430 A machine using the Nalpha-9-fluorenylmethoxycarbonyl (Fmoc) strategy.
  • Peptides were puri ied by high performance liquid chroma ⁇ tography on a reverse phase C18 column. The purity was 95%.
  • peptides were dissolved in phosphate buffer solution (PBS) at 20 ⁇ g/ml and allowed to adsorb in microtiter wells over night. Each peptide coated well had a control well which was only incubated with PBS, but otherwise treated in the same way. The wells were blocked with 3% (w/v) bovine serum albumin (BSA) and 0.2% gelatin, and were stored frozen until use.
  • PBS phosphate buffer solution
  • BSA bovine serum albumin
  • Results were calculated from averages of differen- ces in absorbance between peptide- and mock-coated wells. A cut-off of 0.4. as chosen to minimize non-specific interference. Absorbances of 98.5% of the determinations with control sera and the various peptides were negative by this criterion.
  • Figure 1 shows the distribution of reactivities to certain peptides with Vietnamese (Z) and Swedish (S) HIV-1 antibody positive sera, and control (C) HIV negative sera, a/ Two peptides from pl7, hxb2 gag 101-122 and hxb2 gag 118-140. b/ Two long peptides from the mid of p24, hxb2 gag 173-233 and hxb2 gag 213-263.
  • Figure 2 shows the correlations between absorbance differences with peptides derived from the C-terminus of gpl20. Open circles denote Swedish and filled circles supraan sera. The dashed regression line pertains to Swedish and the continuous one to cloudsan sera. Absorbance differences from z321 env 490-511 are plotted on the x axis, a/ Correlation with hxb2 env 490-511, b/ with eli env 487-508, c/ with mal env 496-513, d/ with jyl env 497-518.
  • Figure 3 shows the distribution of ratios between absorbance differences of eli env 487-508, mal env 496-513 and jyl env 497-518 and z321 env 490-511. Open circles de ⁇ note Swedish and filled ones supraan sera.
  • Figure 4 shows the correlation between the sum of absorbance differences of peptides which reacted selec ⁇ tively with Brazilan HIV positive sera ( "Zl-selective reactions") and the sum of absorbance differences of pep ⁇ tides which reacted selectively with Swedish HIV positive sera (“SW-selective reactions").
  • Figures 5-13 show the ratio of absorbance difference for different pairs of peptides in Swedish, schoolsan and Kenyan HIV-1 positive sera.
  • Figure 5 shows that Swedish sera react preferentially with the P R modified eli V3 sequence.
  • Figure 6 shows that African sera react more strongly with the mal V3 peptide than either Swedish or cloudsan HIV-1 positive sera.
  • Fig 7 shows that African sera react more strongly with the jyl V3 peptide than either Malawian or Swedish HIV-1 positive sera.
  • Figure 8 shows that Swedish sera reacts relatively less with the modified jyl peptide than with the mn peptide.
  • Figures 9-11 concern creating of chimaeric peptides by systematic changes in the V3 region and show the absorbance difference between different peptides in Swedish, cloudsan and Kenyan HIV-1 positive sera.
  • Figures 12-13 concern peptides from the V3 NT loop and show the absorbance difference for a pair of peptides in Swedish, cloudsan and Kenyan HIV-1 positive sera.
  • Table la-c shows the result of scree ⁇ ning for antigenicity and differential reactivity versus Moscowan and Swedish HIV-1 antibody positive sera with a number of synthetic peptides of which some had sequences from African isolates and some from the north American hxb2 prototype isolate.
  • Table 4 shows the degree of selectivity obtained with single peptides or a combination of two peptides for Swedish, Moscowan and Kenyan sera.
  • Synthetic peptides evaluated for differential reactivity with Swedish and Colombiaan sera. An absorbance difference cutoff of 0.3 was used. Peptides derived from African HIV-1 strains.
  • HIV-1 jyl env 308-342 CTRPDNKITRQSTPI- -GLGQALYTTRIK-GDIRQAYC
  • HIV-1 jyl env 497-518 RIEPLGIAPTRAKRRVVEREKR 15/20 5/20 0/29 0.002 s HIV-1 jyl env 497-518 E->Q RIEPLGIAPTRAKRRVVQREKR HIV-1 jyl env 592-610 SYLKDQQLLGIWGCSGKHI HIV-1 jyl env 660-682 QEKNEQDLLQLDKWASLWNWFSI 5/20 5/20 0/16 ns ns HIV-1 jyl env 848-863 LHIPRRVRQGLERALL
  • HIV-1 mal env 301-334 CTRPGNNTRRGIHF- -GPGQALYTTGIV-GDIRRAYC
  • HIV-1 z3 env 580-598 RYLESQQLLGLWGCSGKLI
  • HIV-1 hxb2 gag 384-404 RNQRKIVKCFNCGKEGHTARN 0/18 0/20 0/10 ns ns ns HIV-1 hxb2 gag 387-401 RKIVKCFNCGKEGHT 1/18 6/20 1/24 0.06 ns ns
  • HIV-1 hxb2 env 726-741 DRPEGIEEEGGERD
  • HIV-1 hxb2 env 728-746 HIV-1 hxb2 env 728-746 DRPEGIEEEGGERDRDRSI
  • HIV-1 hxb2 env 758-773 DDLRSLCLFSYHRLRD
  • HIV-1 hxb2 env 841-856 RHIPRRIRQGLERILL
  • HIV-1 mn env 301-335 CTRPNYNKRKRIHI--GPG- RAFYTTKNIIGTIRQAHC
  • ox in “318-378ox” refers to the oxidised form of peptide HIV-1 gag 318-378 (see materials a methods).
  • HIV-l z3 env 293-326 CTRPGSDKKIRQSIRIGPGKVFYAK-
  • HIV-l jyl env 308-342 CTRPDNKITRQSTPI-GLGQALY - TRIK-GDIRQAYC 1/26 2/27 12/26 2/27
  • HIV-l eli env 297-330 CARP-YQNTRQRTPI-GLGQSLYT- TRSRS-IIGQAHC 4/43 0/22 8/22 2/25
  • HIV-l mal env 301-334 CTRP-GNNTRRGIHF-GPGQALYTT-
  • HIV-l eli env 297-330 CARP-YQNTRQRTPI--GLGQSLYT- TRSRS-IIGQAHC 4/43 0/22 8/22 2/25
  • HIV-l hxb2 gag 384-404 RNQRKIVKCFNCGKEGTARN HIV-l mal gag 391-410 KGQKRI-KCFNCGKEGHLARN HIV-l rf gag 384-404 RDQRKIVKCFNCGKVGHIAKN
  • HIV-l hxb2 env 642-665 IHSLIEESQNQQEKNEQELLELDK
  • HIV-l jyl env 660-682 QEKNEQDLLQLDKW- ASLWNWFSI 5/18 5/20 0/16 ns
  • HIV-l hxb2 env 728-746 DRPEGIEEEG-
  • HIV-l hxb2 env 841-856 RHIPRRIRQGLERILL 0/17 7/20 1/24 0.008 ns ns HIV-l mn env 841-856 LHIPTRIRQGLERALL HIV-l z3 env 837-852 LNIPRRIRQGFERALL HIV-l jyl env 848-863 LNIPRRVRQGLERALL
  • V3 jyl/mn >0.5 1/25 17/25 10 -6 mal/mn >1.0 2/26 17/26 10 -5
  • the Colombian and the African sets of sera could be differentiated by cal ⁇ culation either of jyl V3/mn V3 or of mal V3/ mn V3 reactivity ratios.
  • Brazilan and Swedish sera showed differences primarily in the gpl20 C-terminal, V3 gp41 C-terminal and p24 N terminal peptides.
  • Kenyan and Swedish sera differed most clearly in jyl V3/mn V3 and mal V3/mn V3 ratios.
  • these simple peptide-based serolo- gical tests utilizing diagnostic antigens consisting of at least one of the peptides according to the invention could provide a convenient way to obtain useful epidemiological information, and possibly information medically useful for a single patient.
  • the diagnostic antigen(s) containing the peptides according to the present invention has ability to diffe ⁇ rentiate between different sera from african HIV-l infec ⁇ ted persons and also between sera from African and non- African HIV-l infected persons in an immunoassay.
  • the immunoassay used for said discrimination is at least one in the group consisting of an enzyme immunoassay (EIA), radioimmunoassay (RIA), immunoassay involving metal labelling, fluorescence immunoassay (FIA) or an immuno ⁇ assay in which the peptide is soluble and inhibits another reaction.
  • EIA enzyme immunoassay
  • RIA radioimmunoassay
  • FIA fluorescence immunoassay
  • the peptides are used in combination with each other to acheive a maximal degree of selecti ⁇ vity.
  • a serum which reacts stronger with the jyl than with the z321 variant of the C-terminus of gpl20, and reacts relatively strongly with the jyl variant of V3 relative to the mn variant has a African type of serolo- gical reactivity and the person may be infected with a virus belonging to the jyl branch of the African HIV-l tree.
  • HIV-l infections differs serologically in different geo ⁇ graphical locations. Differences occur not only between African and non-African sera but also between sera obtained from southern and east Africa. The differences are especially marked with peptides derived from the primary neutralization determinant, the V3 loop of gpl20, North American variants of this loop are known to elicit neutralizing antibodies and can protect chimpanzees from HIV-l infection (Putney et al).
  • the vaccine composition according to the present invention comprises the diagnostic antigen(s) in an amount effective to protect a subject from diseases caused by African HIV-strains.
  • the vaccine composition further comprises an antigen adjuvant in an amount which together with an amount of said antigen(s) is effective to protect a subject from diseases caused by African HIV-strains.
  • the one-letter symbol for the amino acids was used herein according to the following table.

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Abstract

Peptides, antigènes diagnostiques et composition vaccinale les contenant, et procédé de dosage immunologique permettant de discriminer entre les sérums contenant des anticorps dirigés contre les diverses souches africaines du VIH-1, et entre les souches africaines et non africaines de celui-ci, l'un au moins dudit ou desdits antigène(s) diagnostique(s) étant ajouté pendant le dosage immunologique à un sérum de VIH-1 diagnostiqué de manière positive, et la discrimination étant établie en fonction des réactions sélectives dudit ou desdits antigène(s) avec les anticorps présents dans le sérum.
PCT/SE1992/000423 1991-06-13 1992-06-15 Nouveaux peptides gag et env du vih-1, diagnostic WO1992022572A1 (fr)

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SE9101863A SE9101863D0 (sv) 1991-06-13 1991-06-13 Peptider, diagnostiskt antigen, vaccinkomposition och foerfarande foer selektering av hiv-stammar
SE9101863-0 1991-06-13

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Publication number Priority date Publication date Assignee Title
WO1995033768A1 (fr) 1994-06-08 1995-12-14 Nearmedic Plus Prophylaxie du sida
WO2007039458A3 (fr) * 2005-09-21 2007-06-07 Cytos Biotechnology Ag Conjugues peptidiques du vih et leurs utilisations
EP1855112A1 (fr) * 2006-05-10 2007-11-14 Inserm Procédé de criblage de composés d'inhibition la formation de HIV-1 virions
EP1878742A3 (fr) * 2000-09-04 2008-04-30 Bionor Immuno AS Peptides VIH, antigènes, compositions de vaccin, immunoessai et procédé pour détecter des anticorps induits par le VIH
AP2338A (en) * 2003-09-11 2011-12-16 Victor Anomah Ngu A vaccine

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NATURE, Vol. 329, 1987, E. NORRBY et al., "Discrimination between Antibodies to HIV and to Related Retroviruses using Site-Directed Serology", p. 248-50. *
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WO1995033768A1 (fr) 1994-06-08 1995-12-14 Nearmedic Plus Prophylaxie du sida
AU689266B2 (en) * 1994-06-08 1998-03-26 Rupert Donald Holms Preparations for the treatment of Aids comprising peptides derived from a human protein Ezrin
US5773573A (en) * 1994-06-08 1998-06-30 Holms; Rupert HIV peptides
RU2127599C1 (ru) * 1994-06-08 1999-03-20 Ниармедик, Лтд. Композиция для профилактики и лечения спида, или системной красной волчанки, или связанных с ними нарушений
EP1878742A3 (fr) * 2000-09-04 2008-04-30 Bionor Immuno AS Peptides VIH, antigènes, compositions de vaccin, immunoessai et procédé pour détecter des anticorps induits par le VIH
US7612168B2 (en) 2000-09-04 2009-11-03 Bionor Immuno As Modified HIV peptides, antigens, compositions, immunoassay kit and a method of detecting antibodies induced by HIV
JP2011219481A (ja) * 2000-09-04 2011-11-04 Bionor Immuno As Ｈｉｖペプチド、抗原、ワクチン組成物、ｈｉｖにより誘発される抗体を検出するためのイムノアッセイキット及び方法
AP2338A (en) * 2003-09-11 2011-12-16 Victor Anomah Ngu A vaccine
WO2007039458A3 (fr) * 2005-09-21 2007-06-07 Cytos Biotechnology Ag Conjugues peptidiques du vih et leurs utilisations
EP1855112A1 (fr) * 2006-05-10 2007-11-14 Inserm Procédé de criblage de composés d'inhibition la formation de HIV-1 virions
WO2007128806A3 (fr) * 2006-05-10 2008-01-10 Inst Nat Sante Rech Med Procédés destinés au criblage in vitro de composés inhibant la production de virions infectieux du vih-1 et composés sélectionnés par ledit procédé

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