WO2009043155A2 - Epitopes gag et env distincts du vih-1 d'allèles du système hla associés à une réceptivité différente à l'infection par le vih-1 - Google Patents

Epitopes gag et env distincts du vih-1 d'allèles du système hla associés à une réceptivité différente à l'infection par le vih-1 Download PDF

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WO2009043155A2
WO2009043155A2 PCT/CA2008/001736 CA2008001736W WO2009043155A2 WO 2009043155 A2 WO2009043155 A2 WO 2009043155A2 CA 2008001736 W CA2008001736 W CA 2008001736W WO 2009043155 A2 WO2009043155 A2 WO 2009043155A2
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seq
hiv
infection
peptide
hla
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WO2009043155A3 (fr
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Ma Luo
Francis Plummer
Terry Blake Ball
Sandy Koesters
Christina Semeniuk
Thomas Bielawny
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Canada Minister of National Health and Welfare
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Canada Minister of National Health and Welfare
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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

  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immunodeficiency Syndrome
  • a method of preparing a reagent for inoculating an individual against an HIV infection comprising mixing at least one resistance-linked peptide having an amino acid sequence as set forth in any one of SEQ ID Nos 1-32 or natural variant thereof with a suitable adjuvant, excipient or carrier
  • the reagent is free of peptides having an amino acid sequence as set forth in any one of SEQ ID Nos 33-124
  • the peptide may have an amino acid sequence as set forth in any one of SEQ ID Nos 1-12 or as set forth in any one of SEQ ID Nos 6-12 or as set forth in SEQ ID No 1 or as set forth in SEQ ID No 6 or natural variants thereof
  • a reagent comprising a peptide consisting of or consisting essentially of an amino acid sequence as set forth in SEQ ID Nos 1 -32 or a naturally occurring variant thereof, at least one MHC class I molecule, and a detectable label
  • a reagent comprising a peptide consisting of or consisting essentially of an amino acid sequence selected from the group consisting of any one of SEQ ID Nos 33-124, at least one MHC class I molecule, and a detectable label
  • FIG. 3 B*0701-APRKKGCWK and B*0702-S P RTLNAW tetramer staining showed that the tetramer binds to the intended CD8+ T cell population expressing HLA class I at a frequency of ⁇ 1 % Using a multicolor flow cytometry panel, along with CD3 and CD8 to gate out our populations of interest, we also costained with CD62L and CD45RA These markers are used to phenotypically define distinct subsets of T cells, including Naive (CD62L+ CD45RA+), Effector (CD62L- /CD45RA+/) and Central memory cells (CD62L+/CD45RA-) These various subsets have distinct functional and phenotypic profiles
  • FIG. 4 A schematic drawing of a MHC (HLA in humans) tetramer consisting of Avidin, 4 MHC (HLA) class I molecules and 4 peptide epitopes binding to the MHC (HLA) class I molecules Table 1 HLA genotypes associated with resistance or susceptibility to HIV infection
  • HLAs Human Leukocyte Antigens
  • HLA molecules are central in regulating the immune response through the binding and presentation of peptides known as epitopes derived from self and foreign proteins to T cells.
  • the genes coding for HLA are extremely polymorphic. This genetic diversity ensures that no pathogens can escape detection at the population level. For instance, homozygosity for class I HLA alleles, which limits the breadth of the Cytotoxic T Lymphocyte (CTL) response, has been shown to accelerate disease progression and increase susceptibility to HIV infection [13].
  • CTL Cytotoxic T Lymphocyte
  • HLA class I and class Il antigens regulate immune responses through binding and presenting antigens to CD8+ and CD4+ T cells
  • the associations of HLA alleles with different outcomes of HIV-1 infection are most likely due to the differences in the antigenic peptides or epitopes of HIV being presented and the resulting immune responses that are engaged following immune recognition.
  • HLA genotypes play an important role in susceptibility and resistance to HIV-1 infection. While several group have identified HLA types that seem to protect against disease progression, we have identified several that protect against infection and also against disease progression.
  • the traditional methods for epitope identification include algorithmic identification, peptide elution, and cell-based binding assay techniques.
  • the low throughput, poor reproducibility, labour intensity, and restriction to only the most commonly studied MHC types have impeded the success of these methods.
  • the iTopia ® Epitope Discovery System by Beckman Coulter is a cell free system that can be used to identify, rapidly and reproducibly, epitopes for specific HLA alleles. The identified epitopes can then be confirmed with patient samples using ELISPOT and cytokine flow cytometry (CFC) assays.
  • CFC cytokine flow cytometry
  • HLA*A0101 recognized fewer peptides than B * 0702 (Tables 2-4).
  • B * 0702 a total of 12 peptides including 7 peptide variants were recognized by A*0101
  • 29 peptides were recognized by B * 0702.
  • 1820 peptides overlapping HIV-1 env 63 peptides were recognized by B*0702, whereas A * 0101 recognizes only 20 peptides and peptide variants.
  • a purified or isolated peptide consisting of or consisting essentially of or comprising an amino acid sequence selected from the group consisting of (N/S/H)S(S/N)(K/Q)VS(Q/R)NY (SEQ ID No 1), GTEELRSLF (SEQ ID No 2), TTEGCQQIM (SEQ ID No 3), YVDRFFKTL (SEQ ID No 4) and KTGTEELKS (SEQ ID No 5)
  • N/S/H)S(S/N)(K/Q)VS(Q/R)NY is a consensus sequence of NSSKVSQNY (SEQ ID No 6), SSSKVSQNY (SEQ ID No 7), NSSQVSQNY (SEQ ID No 8), HSNQVSQNY (SEQ ID No 9), HSSQVSQNY (SEQ ID No 10), NSSQVSRNY (SEQ ID No 1 1 ) and SSSQVSQNY (SEQ ID No 1), GTEELRSLF (SEQ ID No 2),
  • a purified or isolated peptide consisting of or consisting essentially of or comprising an amino acid sequence selected from the group consisting of: GTMLLGMLM (SEQ ID No. 13); CSAAENLWV (SEQ ID No. 14); PTDPNPQEI (SEQ ID No. 15); VTENFNMWK (SEQ ID No. 16); VTEEFNMWK (SEQ ID No. 17); VTINCTRPY (SEQ ID No. 18); RIGPGQAFY (SEQ ID No. 19); PIGLGQALY (SEQ ID No. 20); FNCGGEFFY (SEQ ID No. 21 ); ISNYTDIIY (SEQ ID No.
  • these peptides correspond to regions of the env protein that are linked to a protective immune response. Accordingly and as discussed herein, such peptides can be used as a component of an HIV vaccine arranged to elicit a protective immune response against HIV infection and/or disease progression.
  • a set of purified or isolated peptides which consisting of or consisting essentially of a naturally occurring variant of any one of the resistance-linked peptides, that is, having an amino acid sequence as set forth in any one of SEQ ID Nos 1-32. Exemplary examples of such variants are provided in the accompanying table. As discussed herein, these peptides can be used as a component of an HIV vaccine arranged to elicit a protective immune response against HIV infection and/or disease progression.
  • a method of preparing a reagent for immunizing or inoculating an individual against an HIV infection comprising mixing one or more of the resistance-linked peptides as set forth in any one of SEQ ID Nos 1-32 with a suitable adjuvant and/or excipient and/or carrier.
  • the above-described peptides can also be used to monitor immune response or aid in HIV clinical care and treatment. Specifically, an individual producing antibodies against a resistance-linked peptide is producing a protective immune response.
  • a reagent comprising: a peptide consisting of or consisting essentially of an amino acid sequence as set forth in SEQ ID Nos. 1-32 or a naturally occurring variant thereof; at least one MHC class I molecule, and a detectable label
  • the reagent may comprise an MHC tetramer, which are reagents consisting of four MHC class I molecules bound to the HIV peptide of interest, linked together by a detectable label or agent, for example but by no means limited to a fluorescently labeled streptavidin molecule
  • MHC tetramers will bind specifically to the TCR of all T cells that recognize that particular MHC/peptide complex This is a very powerful tool for precise, easy, and rapid enumeration of antigen-specific T cells
  • HLA class I tetramers can bind with sufficient avidity to HIV-specific CD8 + T cells to allow their detection by flow cytometry
  • MHC tetramers have been used extensively to visualize antigen- specific T-cell immunity in humans and in animal model systems Since the discovery of M H C- restricted recognition of peptide antigens by T cells, a main aim has been to visualize disease- and vaccine-induced T-cell immunity We have shown in the provided
  • a number of epitopes recognized by B * 0702 are provided These include gag epitopes IVQNAQGQM (SEQ ID No 33), SPRTLNAWV (SEQ ID No 34), TPQDLNMML (SEQ ID No 35), IVGGHQAAM (SEQ ID No 36), RLRPGGKKK (SEQ ID No 37), GPIPPGQMR (SEQ ID No 38), TPQEQIGWM (SEQ ID No 39), VRMYSPVSI (SEQ ID No 40), YVDRFFKTL (SEQ ID No 41), RALGPGATL (SEQ ID No 42), GPGATLEEM (SEQ ID No 43), GPGHKARVL (SEQ ID No 44), GPSHKARVL (SEQ ID No 45), KARVLAEAM (SEQ ID No 46), QANANTAIM (SEQ ID No 47), QAQQPNVMM (SEQ ID No 48), QVNGNTAIM (SEQ ID No 49), QVQHTNIMM (SEQ ID No 33), S
  • HIV-1 infection HLA-B * 0702 with susceptible to HIV-1 infection through the study of highly exposed sexworkers in the Pumwani sexworkers cohort. Women who are A * 0101 positive are more likely to be HIV-1 uninfected under highly exposed conditions, whereas women who are B*0702 positive are more likely to be infected in the Pumwani sexworker cohort. Furthermore, HIV-1 infected B * 0702 positive Caucasians also have higher viral load and rapidly progress to AIDS.
  • A*0101 positive women are more likely to be uninfected under the highly exposed conditions and the A*0101 only recognizes a few and unique epitopes in HIV-1 gag and env protein, the protective immune responses correlate to fewer epitopes, narrow in spectrum, specific in location of the epitopes.
  • B * 0702 positive women are more likely to be HIV-1 positive and once infected are more likely to have higher viral load and rapidly progress to AIDS and B * 0702 recognize many epitopes with high affinity, low off-rate in HIV-1 gag and env proteins, thus accounting for the unprotective immune response or immune failure or harmful immune responses correlated to many epitopes and wide spectrum.
  • the correlates of protective or bad immune response to HIV-1 infection provides a guide to develop and test effective vaccines for HIV-1 and the tools, such as tetramers constructed with the specific alleles and peptides can be used to monitor the effective of the vaccination.
  • the specific peptides can be used as components of peptide-based vaccines.
  • a reagent comprising: a peptide consisting of or consisting essentially of an amino acid sequence selected from the group consisting of any one of SEQ ID Nos. 33-124; at least one MHC class I molecule; and a detectable label.
  • a method of preparing a reagent for immunizing or inoculating an individual against an HIV infection comprising mixing one or more of the resistance-linked peptides as set forth in any one of SEQ ID Nos 1-32 or natural variant thereof with a suitable adjuvant and/or excipient and/or carrier with the proviso that the reagent is free of peptides having an amino acid sequence as set forth in any one of SEQ ID Nos 33-124
  • the B*0702 epitopes as components of tetramers can be used to monitor failed vaccine responses, or to identify immunologic failure in terms of patient care and treatment That is, Individuals recognizing 'bad' epitopes may need different clinical care compared to those recognizing 'good' immune responses, as discussed herein Accordingly, the inventors believe that this represents a novel strategy for
  • the HIV vaccine should include only a narrow spectrum of peptides, such as the A * 0101 epitope that is located at the protease cleavage site of p17/p24, in the critical site of env N- terminal and/or any one of the peptides as set forth in SEQ ID Nos 1-32 Immune responses generated against these epitopes or multiple copies of these epitopes can be expected to provide sufficient protection
  • the B * 0702 epitopes should be avoided in HIV-1 vaccine and measures that can neutralize or block the immune recognition of B * 0702 epitopes should be used in conjunction of the HIV-1 vaccination While not wishing to be bound to a particular theory or hypothesis, the inventors note that since HIV-1 cannot efficiently infect and replicate in resting T cells, immune activation by recognition of multiple epitopes with high affinity and low off-rates will provide more targets and conditions for HIV-1 infection and replication The large number and wide spectrum of gag peptides recognized by B * 0702 will result in a wider spectrum
  • a method for preparing a medicament for use in inoculation or immunization of an individual in need of such treatment comprising mixing one or more of the resistance-linked peptides as set forth in any one of SEQ ID Nos 1-32 or natural variant thereof with a suitable adjuvant and/or excipient and/or carrier
  • the resistance-linked peptides (SEQ ID Nos 1-32) and/or the susceptibility-linked peptides (SEQ ID Nos 33-124) or natural variants thereof may be incorporated into a panel or chip or other such support for the monitoring or assessing of the immune response of an individual to a vaccination or treatment for HIV infection or for providing an overview of possible disease progression in an individual Specifically, by using such a panel, one can determine whether the immune system of the individual will be largely protective or susceptible to the HIV infection
  • NSSKVSQNY variants that present in the consensus sequences of major HIV-1 subtypes and shown that the recognition of A * 0101 to the consensus sequence variants of major HIV-1 subtypes (Table 2) This would suggest that the application of the invention to different HIV-1 subtypes We could presume (as would any skilled in 'the art' that variants of this peptide that can be presented by A0101 or other protective HLA types could also be used for this strategy This would include naturally occurring variants of NSSKVSQNY (Table 2) as well as any peptides that may be longer or shorter and still capable of being presented by A0101 class I epitope that still contain the NSSKVSQNY (SEQ ID No 6) or its variants motif or an amino acid sequence as set forth in any one of SEQ ID Nos 1-32
  • a high resolution sequence-based HLA typing method was used to type HLA class I genes and a two-step sequence-based method was used to type DRB genes[24, 25].
  • Ambiguous allele combinations were resolved by sequencing with sequence-specific primers Since only exon 2 and exon 3 of class I genes are involved in the peptide binding grove, we did not attempt to resolve class I alleles that differ beyond exon 2 and exon 3 DRB genes were screened by a first round of sequence analysis, and high resolution typing was carried out for the DRB1 * 01 group that was previously associated with resistance to HIV-1 infection
  • Three independent quality control procedures for HLA typing were established to ensure accuracy HLA class I genes and DRB1*01 and DRB1 * 1503 subgroups are typed to the four-digit resolution and subsequently reduced to either a two-digit classification in order to compare
  • Overlapping peptides were designed in sequences of 9 amino acid residues overlapping by 8, to span the entire HIV-1 gag polyprotein region. A total of 609 peptides were synthesized. A * 0101 and B * 0702 iTopia kits were purchased from Beckman Coulter and the peptides were screened following protocols provided by the supplier. Once positive binding was identified, affinity and off-rate assays were conducted with the iTopia epitope discovery system. The affinity and off-rate of the peptide binding by the A * 0101 and B * 0702 were determined.
  • PBMC peripheral blood mononuclear cells
  • the challenge in selecting the "right" immunogenic proteins is a major obstacle to the development of cell-mediated vaccines
  • the iTopia ® Epitope Discovery System was recently developed by Beckman Coulter to identify, rapidly and reproducibly, epitopes for specific HLA alleles
  • the fundamental units of the iTopia ® system are assembled tetramers — consisting of properly folded complexes of specific MHC molecules, beta 2 microglobulin and placeholder peptides — which are bound to both streptavidin- coated microplate wells and a fluorescent-labelled antibody designed to recognize only a properly folded peptide/MHC complex
  • Overlapping peptides spanning the protein of interest or protein region of interest are synthesized
  • a binding assay is performed for each of

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Abstract

Le profil de liaison peptidique de deux allèles de la classe 1 du système HLA, A*0101 et B*0702, qui sont associés à des résultats différents en matière d'infection par le VIH-1, a été étudié. HLA-A*0101 est fortement associé à des femmes résistant au VIH-1 (p=0,016, risque relatif approché: 1,7, 95% CI:1,1-2,7), et le HLA-B*0702 est associé à une réceptivité à l'infection par le VIH-1.
PCT/CA2008/001736 2007-10-03 2008-10-03 Epitopes gag et env distincts du vih-1 d'allèles du système hla associés à une réceptivité différente à l'infection par le vih-1 Ceased WO2009043155A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012135959A1 (fr) * 2011-04-07 2012-10-11 Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Health Peptides de site de clivage de protéase comme vaccin contre le vih

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WO1991008227A1 (fr) * 1989-11-27 1991-06-13 Replico Medical Aktiebolag NOUVEAUX PEPTIDES p17 DU VIH-1, ANTIGENES DE DIAGNOSTIC ET PROCEDE D'IMMUNOANALYSE
US9340577B2 (en) * 1992-08-07 2016-05-17 Epimmune Inc. HLA binding motifs and peptides and their uses
ES2265165T3 (es) * 1997-07-10 2007-02-01 Mannkind Corporation Dispositivo para inducir una respuesta ltc.
WO2001024810A1 (fr) * 1999-10-05 2001-04-12 Epimmune Inc. Induction de reponses immunitaires cellulaires au virus de l'immunodeficience humaine de type 1 a l'aide de compositions de peptides et d'acides nucleiques
WO2004002415A2 (fr) * 2002-06-27 2004-01-08 Dana-Farber Cancer Institute, Inc. Compositions et methodes de modulation d'une reponse immunitaire avec les lymphocytes t cytotoxiques
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012135959A1 (fr) * 2011-04-07 2012-10-11 Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Health Peptides de site de clivage de protéase comme vaccin contre le vih
EP2694654A4 (fr) * 2011-04-07 2016-03-02 Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Health Peptides de site de clivage de protéase comme vaccin contre le vih
US10285942B2 (en) 2011-04-07 2019-05-14 Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Health Methods of inducing an immune response against HIV by administering immunogenic peptides obtained from protease cleavage sites
US10617645B2 (en) 2011-04-07 2020-04-14 Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Health Nanoparticles carrying immunogenic peptides targeting HIV-1 protease cleavage sites
US11389527B2 (en) 2011-04-07 2022-07-19 Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Health Methods of inducing an immune response against HIV-1 utilizing nucleic acids encoding polypeptides containing HIV-1 protease cleavage sites

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