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Towards a therapeutic vaccine to reduce HIV reservoir, both neutralizing HIV and inhibiting effector T cells depletion Pr. Patrice DEBRE Laboratoire Immunité & Infection INSERM UMR-S 945 Hôpital Pitié-Salpêtrière Paris, France “Towards an HIV Cure” Pre-Conference Symposium 20 & 21 July 2012
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A strategy to decrease HIV reservoir INFECTION Virus Infected CD4 cells PATHOGENESIS NK Non-infected CD4 cells Vaccine Virus Neutralization Restore Immune-response
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An epitope based vaccine, both 1) Inhibiting the deleterious effect of NK cells A NK ligand on CD4+ T cells ? 2) Neutralizing HIV-1
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NKp44L is induced during HIV infection by the 3S/gp41 motif
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gC1qR is the cell-surface receptor of the 3S/gp41 motif on CD4+ T cells HK 3S C1q C3 NA 0255075100125150175 NKp44L expression (MFI) NKp44L expression IgM NA 3S 3S+ agC1qR Role of gC1qR ! Listeria monocytogenes Staphylococcus aureus Plasmodium falciparum HCV, rubella virus, HSV and HTNV Fausther-Bovendo et al PLoS Pathogens 2010 Deleterious effect of NK cells ?
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Anti-3S Ab : a predictive value for the evolution of the disease ? 0 100 200 300 04008001200 Anti-3S (U/mL) CD4 count/mm 3 Vieillard et al AIDS (2006) Unpublished data Multivariate study between 40 patients (first quartile) with a slope CD4>2.7/month and 40 patients (last quartile) with slope CD4<-6.9/month VariableOdds-ratio IC 95 P Sexe M W Age (10y) CD4 (X100) Log VL 3S Ab (x100) 1.00 1.83 1.30 0.58 1.17 2.89 0.049-6.87 0.76-2.23 0.42-0.81 0.55-2.51 1.60-5.17 0.372 0.334 0.001 0.682 <0.001
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Summary-1 - NKp44L is specifically expressed on non infected CD4+ T cells from HIV-1 patients; - NKp44L is induced by a specific peptide from the gp41 HIV-1 protein; - Anti-3S antibodies are predictive of the disease evolution.
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A 3S vaccine inhibiting HIV pathogenesis 1- Macaque model of SHIV infection (Vieillard et al, AIDS 2008) 2- Prophylactic vaccination (Vieillard et al, PNAS 2008) 3- Therapeutic vaccination (Vieillard et al, submitted) Proof of concept in macaques Collaboration: Roger Le Grand (CEA, Fontenay-aux-roses; France)
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Prophylactic vaccination by the 3S-gp41 peptide Vieillard et al Proc Natl Acad Sci USA (2008) D385 Infection SHIV 162P3 D0 Immu 1 D30 Imm. 2 D60 Imm. 3 D585 Animal groups : Analysis: Anti-3S antibodies Plasma viral load Blood lymphocyte phenotyping NK & CD4 activation Cytotoxicity Apoptose Inflammation Sacrifice Study design KLH-control macaques : 3S-immunized macaques :
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Effect of 3S vaccination on Viral load, NKp44L expression, and CD4 count CD4 / mm 3 0 500 1000 1500 2000 050100150200 ** * Viral load 1 10 2 10 4 10 6 10 8 050100150200 NS 0 10 20 30 40 50 0 100150200 % CD4 + NKp44L + 0 500 1000 1500 -400 -2000 200 anti-3S (U/mL) 3S SHIV 162P3 Days post-infection KLH-control macaques3S-immunized macaques 3S
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Effect of 3S vaccination on CD4 activation & Inflammation
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Summary-2 Immunogenicity in cynomolgus (anti 3S response) BUT Unchanged viral load Decreased NKp44L expression on CD4 + T cells Decreased NK cells cytotoxicity on CD4 + T cells Decreased CD4 + T cells apoptosis Preservation of CD4 + T cell counts Decreased immune activation Decreased inflammation during the acute phase
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Summary Epitope 3S (SWSNKS) CD4 + T cell HIV infected cells HIV virion gp41 NKp44L CD4 + T cell lysis Autologous NK cells Anti-3S Ab NKp44 CD4 + NKp44L + cell E/T ratio 0 10 20 30 40 100/150/125/112.5/1 44L + 44L - % NK Lysis CD4 depletion Cell activation Inflammation
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An epitope based vaccine, both 1) Inhibiting the deleterious effect of NK cells 2) Neutralizing HIV-1 Search for an effect of 3S mutant NH2-SWSNKS-NH2 Alanine scanning
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HIV infectivity of 3S mutants Infectivity 0 25 50 75 100 WT S613A W614A S615A N616AK617A S618A % p24 production Entry % -galactosidase activity 0 25 50 75 100 WT S613A W614A S615A N616AK617A S618A
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Neutralizing effect of anti-3S mutant Abs 200 100 50 150 0 0 5101520 Ig ( g/ml) 200 100 50 150 0 Human Abs Mice Abs 200 100 50 150 0 0 5101520 Ig ( g/ml) p24 (ng/ml) 0 0 4 6 810 Days post-infection 2 200 100 50 150 p24 (ng/ml) WAWA WAWA WT W/o Ab #109 p24 (ng/ml) 0 4 6 810 Days post-infection 2
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Antibodies against 3S (W A) mutants also inhibit NK pathogenesis NT 3S WT #117#24 #44 #65 #71 #109 NKp44L 68.3 6.4 21.934.628.4 21.931.3 22.7 CD107a NT 3S WT 38.3 58.2 2.9 0.6 29.4 34.1 28.6 7.9 32.164.2 2.1 1.6 #117 #24 #44 30.3 55.1 1.8 40.9 52.1 4.9 2.1 29.9 61.0 7.7 1.4 #65#71 #109 NKp44 30.4 62.6 5.9 1.1 36.4 55.0 6.3 2.3 34.9 55.4 7.8 1.9
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Conclusion 1) Restoring/preserving CD4 cell functions A gp41 epitope based vaccine, both 2) Neutralizing HIV-1 As a tool to decrease HIV reservoir
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In Progress … Animal Model Clinical trial Phase I/IIa HIV-1 infection Non-infected AIDS Asymptomatic phase Therapeutic Vaccine Antiretroviral Therapy
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Unité Immunité & Infection Team-2 Patrice Debré Hugues Fausther Bovendo Caroline Petitdemange Alexis Sennepin Abla Achour Florence Baychelier Vincent Vieillard Team-1 Brigitte Autran Assia Samri Unité Epidémiologie Clinique Dominique Costagliola Service de Virologie Henri Agut Vincent Calvez Daniel Candotti Isabelle Malet Service des Maladies Infectieuses & Tropicales Christine Katlama Hôpital Pitié-Salpêtrière - Paris Institut Pasteur Olivier Schwartz Nathalie Sol-Foulion Felix Rey CEA Laboratoire d’ Immuno-Virologie Roger Le Grand Nathalie Deudreude-Bosquet Aurélien Corneau Isabelle Mangeot-Méderlé … Grants ANRS Sanofi-Pasteur Bill & Melinda Gates Foundation Agence Nationale de Recherche (ANR) InnaVirVax ORVACS Partners
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