HIV gp120 C5 region as a target for a therapeutic vaccine
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Slide 1 :
The C5 region of HIV-1 gp120 binds peptides; ? target for a therapeutic vaccine Angus Dalgleish Oncology/Cellular and Molecular Medicine, SGUL
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Clinical course: CD4+ Count and Viral load in HIV/AIDS
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Background to HIV induced AIDS HIV induces AIDS in a majority of infected humans but not all (eg. 5-10% are LTNPs). HIV does not induce AIDS in the majority of chimpanzees…….Why? Shared CD4 and the chemokine co-receptors. Cytotoxicity/syncytia induction also observed in chimpanzees.
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What is the major difference between HIV infected chimps and humans? Both have replicating virus in blood and tissue. Chimps have no evidence of chronic immune activation as measured by B2M, Neopterin, sTNFRII, Surface markers, apoptosis and lymph node changes. These changes precede “AIDS” in humans (Gougeon, ML. J Immunol: 1997 March 15). Rare cases of progression in chimpanzees associated with hyper-immune activation (O’Neill,SP. J Inf Dis 2000)
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Immune Activation in HIV+ humans Soluble B2M, sIL-2 and sTNFRII and Surface HLA-DR and CD38 are best activation markers.( J Georgi ) HIV can induce TNF production, resulting in immune activation which leads to CD4 depletion (apoptosis) or dysfunction (Anergy). (Ledermann, AIDS, 2000) Degree of activation correlates with virus load and pathogenesis. ?chicken and egg.
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Lessons from SIV Models Rhesus macaque: High viral load, High activation = Disease progression and AIDS. African green (Agm): Low viral load, Low activation = Non progression/No pathogenesis Sooty mangabey (Sm): High viral load, Low activation = Non progression/No pathogenesis SIV PBj14 - severe ‘acute’ AIDS and death in weeks.....Acute cytokine induced immune activation. Therefore High viral load can be observed against background activation without causing disease. Why does hyperactivation occur in the majority if HIV-1 infected individuals?
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Mechanisms of Immune Panactivation 1. Hypervariability of antigen 2. Superantigens 3. Allostimulation (GVHD)
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HIV-1 variability and disease Variability contributes to immune escape from humoral and cytotoxic T-lymphocyte responses. However greater viral variability is observed amongst Slow/ LTNP than Rapid progressors to AIDS. Similar variability seen in HIV infected chimpanzees. Suggests Variability contributes to immune activation but is unlikely to explain systemic activation induced by HIV. Likely activation/pathogenic element is conserved and effective amongst susceptible hosts.
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Does HIV encode a SuperAntigen (SAg)? Early papers showed both enhanced and deleted V? expression of the T-cell receptor. However, no agreement re specificity. (Westby et al, BJH Sept 1998) showed that low CD4 counts and not SAg effects account for variable V? expression.
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Graft Versus Host Disease (GVHD) T-cells retain high capacity to respond to allogeneic HLA directly or indirectly. 1.Acute - Th-1 cytokines - usually allo HLA presenting self HLA 2. Chronic - Th-2 cytokines - self HLA presenting allo HLA peptides Chronic GVHD is very similar to AIDS.
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Does HIV induce GVHD? cont/.. Similarities: Opportunistic infections, weight loss, lymphadenopathy, lymphomas, skin lesions, pan immune activation with CD4 suppression. Differences: CD4 count never falls to levels seen in AIDS but then cytopathic HIV is not present. NB: Shearer reported similarities before HIV discovered (NEJM 1983)
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How Could ‘HIV’ Induce GVHD? By carrying foreign HLA in oligomers to alloactivate foreign T cells. Structural Mimicry of HLA with/without peptides to stimulate non-specific response. 3. Providing peptides with sequence similarity to HLA for presentation to T-cells by self HLA on APC.
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Evidence for role of virion associated HLA HIV budding through HLA negative cells is non-infectious (Beretta. AIDS 1999, Oct 22). Selective acquisition of HLA-DR by HIV from infected cells (1 - 3 x more than gp120) Virion associated HLA is functional in peptide and SAg presentation. This enhances activation and apoptosis in presence of gp120. HLA on virus may aid CD4+ T cell targeting, activate cells or simply serve as a disguise.
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HIV-1 gp120 interacts with CD4 receptor similar to HLA class 2 present antigen to the T Cell and can directly kill CD4 cells HIV ANTIGEN PRESENTING CELL Virion acquired HLA Chemokine receptor T CELL HLA CD4
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HIV-1 gp120 and HLA Mimicry
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HIV-1 gp120 C5 region as a potential alloepitope The conserved C5 region sequence of gp120 bears sequence and structural homology with amino acids 67-80 of the 3rd hypervariable region (HVR3)of HLA-DR? chain. (Habeshaw et al, 1999) The HVR3 region is associated with antigenic peptide interactions, T-cell regulation and allorecognition. This region therefore represents an alloepitope. C5 peptide is recognised as allogeneic by alloactivated CTLs (Clerici et al, Eur J Immunol. 1993), “Gp120 plus peptide” are recognised by T cells raised against the peptide on HLA A2 (Sheikh et al, Viral Immunol 1999) T cell lines generated against C5 region suppress HLA-DR restricted responses to soluble antigens and are autoreactive against uninfected activated HLA-DR expressing cells. (Wilson et al, AIDS Res Hum Ret 1997)
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The C5 region and the HLA-DR? chain HVR3
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HIV-1 gp120 C5 region and direct HLA structural mimicry Molecular Modeling predicted presence of alpha-helix bearing similarity HLA class I and II antigen binding sites (Hounsell et al 1991,Mol Aspects of Med). Anti-C5 antibodies L31 and M38 crossreact with peptide binding domains of HLA class I alleles (Grassi et al, 1991,J exp med) Peptide binding by soluble gp120 of HLA restricted epitopes (Sheikh et al, 1995, AIDS).
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Predictions from model . - THAT - HLA-B8 would be fast progressors and HLA-B27 slow progressors (Gore MRC) - chimpanzees would have restricted HLA - CTL epitopes same in HIV NP’s as chimps
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130 48.6 94 36.4 HLA-DR1 + Flu pep 29.8 20.6 kDa HLA-A2 restricted signal peptide (KKSALLALMYVCPGKADKE) HLA-DR1 restricted Influenza HA 307-319 (PKYVKQNTLKLAT). Analysis of UV crosslinking to soluble HLA class I and II HLA-A2 + signal pep
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130 94 kDa Lack of peptide binding by Soluble C5 truncated gp120 (?C5.gp120) HXBc2 gp120 ?C5 gp120 HXBc2 gp120 ?C5 gp120 130 94 kDa HLA-DR1 restricted peptide HLA-A2 restricted peptide
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Peptide binding by native gp120 on deactivated non-infectious HIV-1 virions HIV-1 (T1) + P17 HIV-1 (T2) + P17 43 118 75 kDa HIV-1 (T2) + TT HIV-1 (T1) + TT HIV-1(T1) + P17 HIV-1(T1) + TT Class I binding Class II binding Denatured
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SELDI based capture assay MH+/Z HLA-DR1 CD4 HIV-1 IIIb gp120 Peak Intensity HLA-DR1 restricted Influenza HA 307-319 (PKYVKQNTLKLAT). Mw 1503.8 Da Capture Ligands
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HLA-DR1 CD4 HIV-1 IIIb gp120 HIV-2 ROD gp105 Blank HLA-DR1 CD4 HIV-1 IIIb gp120 Peak Intensity Peak Intensity Capture Ligands
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Peptide Capture conserved across multiple HIV-1 envelopes SELDI based capture assays
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75 43 118 200 kDa Interference with peptide binding by Soluble gp120 pre-incubated with Anti-C5 MAb Gp120 + EVA3047 (Anti-V3 Loop MAb) HIV-1 IIIb gp120 Gp120 + EVA3048 (Anti-V3 Loop MAb) Gp120 + D7324 (Anti-C5 polyclonal) Gp120 + 803.15.6 (Anti-C5 MAb)
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HLA-DR1 CD4 HIV-1 IIIb gp120 Gp120 + EVA3047 (Anti-V3 Loop MAb) Gp120 + EVA3048 (Anti-V3 Loop MAb) Gp120 + D7324 (Anti-C5 polyclonal) Gp120 + 803.15.6 (Anti-C5 MAb) Interference with peptide capture by immobilized gp120 pre-incubated with Anti-C5 MAb
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HLA DR1 + Flu peptide Crystal structure and modelling GP-120 DC5-mutant GP120 + Flu peptide
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The gp120 C5 region as a humoral target? Terminal C5 region is exposed and associatiated with non-neutralising antibodies (Palker et al, PNAS 1987) (Vahlne et al, PNAS, 1991) Possible role of C5 region in viral fusion or interactions with cell surface proteins? (Barbouche et al, Virology 2000) (Barbouche et al, AIDS Res Hum Ret, 2002) As a Target against HLA structural mimicry within the envelope ?
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Non-neutralizing response to C5 region is associated with immunological stability Seronegative partners of AIDS patients have antibodies to HLA and/or C5 of gp120 in 70% studied cases. (Brown et al. AIDS 2000) Anti-C5 region antibodies associated with slow progression (Loomis-Price et al, J Infect Dis. 1998) (Lifson AR et al, J Infect Dis 1991) (Warren RQ et al, J Clin Immunol 1991) Loss of anti-C5 humoral response associated with disease progression. (Wong MT et at, JID, 1993)
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Walter Reed Cohort
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?Therapeutic vaccine Data with neutralising antibodies to “tat” - O Picard et al, presented this meeting. Data with T cell responses to “gag”, M sommerfeldt group, Norway. Proposed humoural/T cell response to C5 peptides.
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Continued...…..Anne-Marte et al. AIDS 2006
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Proposal 4 C5 peptides selected for humoural and cell mediated responses. AIM IS TO NEUTRALISE IMMUNE ACTIVATING ABILITY OF HIV. Clinical trials with and without gag vaccine.
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Work by Martin Cadogan With Brian Austin and Jonathon Heeney Special thanks to:- Robin Weiss and Hans Wigzell for examining this work as a PhD thesis for Martin Cadogan and suggesting significant improvements.
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Future work Now funded by a collaborative grant from the MRC Norway to M Sommerfelt, B Sorensen, (Norway). P Kloiez ( Berlin) and A Dalgleish (London).
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