Are we targeting the right HIV determinants?

Transcription

1 QuickTime et un décompresseur TIFF (non compressé) sont requis pour visionner cette image. AIDS Vaccine 2009 October 22 nd Paris Are we targeting the right HIV determinants? Françoise BARRÉ-SINOUSSI Regulation of Retroviral Infections Unit Department of Virology

2 Goals of an Effective HIV Vaccine Protective immunity Sterilizing immunity Abortive infection Viremic control and protection against disease Reduction of HIV transmission in the population Garber DA et al: Lancet Inf Dis 2004;4:

3 Classical desired immune response to HIV-1 vaccine. QuickTime et un décompresseur TIFF (non compressé) sont requis pour visionner cette image. Walker BD and Burton DR; Science 2008

4 Cellular immunity: which epitope to target? Control of Viremia in simian immunodeficiency virus infection by CD8+ lymphocytes - Schmitz JE et al, Science 1999 CD8+ T-cell responses to different HIV proteins have discordant associations with viral load - Kiepiela P et al, Nat Med 2006 Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with gag-specific CD8 T cell responses - Saez-Cirion A et al, J Immunol 2009 Maintenance of HIV-specific CD4+ T cell help distinguishes HIV-2 from HIV-1 infection - Duval MG et al, J immunol 2006 Immunodominant HIV-1 CD4+ T Cell Epitopes in Chronic Untreated Clade C HIV-1 Infection - Ramduth D et al, PloS One 2009 CD8+ and CD4+ T cell gag specific responses Better control of HIV replication

5 Cellular immunity: which epitope to target? Map of known distinctive CD4+ and CD8+ epitopes described in literature and included in the Alamos database across the proteome QuickTime et un décompresseur TIFF (non compressé) sont requis pour visionner cette image. Korber BT, Letvin NL, Haynes BF - J Virology 2009 Candidate Vaccine sequence to represent Intra- and Inter clade HIV-1 variation - Yang OO, PloS One 2009 Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance - Tenzer et al, Nature Immunology 2009

6 Broadly neutralizing Abs: which one is needed? PG9 PG16 b12 gp120 QuickTime et un décompresseur TIFF (non compressé) sont requis pour visionner cette image. gp41 2F5 4E10 2G12 Adapted from Walker LM, Science 2009 Antibodies specific enough to confer protection at modest concentrations Which immunogens to elicit protective antibodies?

7 Lessons from clinical efficacy trials. Dates Clinical efficacy studies Strategy Viral targets Immune response Efficacy AidsVax Protein subunit (AIDSVAX) monomeric rgp120 Type specific binding Ab Step Phambili Viral vector (Ad5) gag/pol/nef CTL - Prime: ALVACvCP152 + Boost:AIDS VAX RV144 (Thai trial) gag/pol/env + Monomeric rgp120 B/E CTL + Type specific binding Ab modest

8 Are we looking for the right responses? bnabs to control the infection target mainly free virus Viral escape T-cell response to control HIV replication Limited by immunodominance Focus on limited number of epitopes Viral escape - Breath and Magnitude of the response? - Long lasting immunity (memory?) -What are the best correlate of protection? - Are we looking for the right responses? - Are we looking at the right place? -What is the best immunogen? -Which other viral deteminant shall be inserted?

9 Are we looking at the right places?? Peripheral immune response Mucosal immune response Differential immunogenicity of vaccinia and HIV-1 components of a human recombinant vaccine in mucosal and blood compartments - Anton PA et al, Vaccine 2008 Gender Differences in Human Immunodeficiency Virus Type 1-Specific CD8 Responses in the Reproductive Tract and Colon following Nasal Peptide Priming and Modified Vaccinia Virus Ankara Boosting- Peacock JW et al, J Virol 2004 HIV-neutralizing immunoglobulin A and HIV-specific proliferation are independently associated with reduced HIV acquisition in Kenyan sex workers Hirbod T et al. - AIDS Everyone, everywhere, in every compartment, whatever the mode of transmission

10 Immune response should protect against HIV-1 invasion in the genital mucosa K.Brolinden, AT.Haase, SK.Ahuja, GM.Shearer & J.Andersson. J. Int. Med

11 From Wu L and KewalRamani V - Nat.Rev. Immunol 2006 Are we controlling cell to cell transmission? QuickTime et un décompresseur TIFF (non compressé) sont requis pour visionner cette image. Glycosphingolipid composition of HIV-1 particles is a crucial determinant for dendritic cell-mediated HIV-1 trans-infection - Hatch SC et al, J Virol 2009 HIV-1 Infection of DC: Evidence for the acquisition of Virus Particles from Infected T Cells by Antigen Uptake Mechanism- Venkatachari NJ et al, PloS One 2009

12 Cell to cell transmission QuickTime et un décompresseur TIFF (non compressé) sont requis pour visionner cette image. From Haller C and Fackler O - Biol Chem 2008 QuickTime et un décompresseur TIFF (non compressé) sont requis pour visionner cette image. Retrovirus can establish filopodial bridges for efficient cell to cell transmission, Sherer NM et al - Nat Cell Biol 2007 HIV-1 env binds to and signals through integrin α4β7, the gut mucosal homing receptor for peripheral T cells, Arthos J et al - Nat Immuno 2008

13 Goal of an HIV-1 Vaccine, according to HIV disease Viral RNA/ml plasma CD4 + counts CD8 + DR + CD38 + Vaccine Immunological setpoint (before seroconversion)?? primary infection Viral setpoint (6 months p.i.) chronic infection Intense generalized T cell activation blood CD4 + AIDS Viral infection, dissemination and Reservoirs Chronic Immune Activation viremia Intestinal CCR5 + CD4 + T memory cells (destruction of GALT, Microbial translocation)

14 What about preventing immune activation? Control of viral infection Measles Hepatitis Polio Vaccines Control of pathogenicity Diphteria Tétanos Cholera HIV-1? Viral determinants implicated in abnormal activation? Ascher MS et Sheppard HW, Clin Exp Immunol 1988 Giorgi JV et al, J Infect Dis 1999

15 Which HIV determinants are involved in pathogenic signals? Viral determinant Env gp120 gp41 Nef Vpr Vpu Tat Pathogenic signals Binding to CD4/CCR5: triggers immune activation? Interaction with unknown receptor? NK cell killing of CD4 T cells by expression of NKp44L Down-regulation of CD4 and MHC I Mediation of cellular signalling and activation Absence of down-regulation of TCR-CD3 Enhance infectivity Apoptosis Induction of cell cycle arrest and apoptosis NK cell killing of infected T cell by expression of NKG2D Counteracts tetherin and enhance virions release Up regulation of cytokine (IL-6, TNF-α) and modulate cellular gene expression apoptosis

16 Learning from Models of natural protection African non human primates African green monkeys Sooty Mangabey Elite controllers Early signals of abnormal T cell activation AIDS, a disease of inflammation Two distinct models of protection against progression to AIDS HIV reservoirs & replication in the host HIV-1 macaque

17 Learning from HIV exposed but uninfected individuals Homozygote CCR5-Δ32 is strongly associated with protection against infection But Other multiple mechanisms have been reported.. Low susceptibility to HIV1 infection related to: Genetic background: Other CCR5 mutations and low CCR5 expression, increased sensitivity to chemokine inhibition Post-entry restriction of HIV-1 infection in target cells Efficient T cell and IgA specific responses NK cell activation associated with modulation of NK cell repertoire (KIR2DL3 expansions; Ratio KIR3DS1/KIR3DL1 increased; Ratio NKG2C/NKG2A increased; Increase expression of CD161 on the surface CD107a+ NK cells) Innate immunity...

18 Learning from Vaccinees (Thai RV144 efficacy trial and future clinical studies.) MORE RESEARCH NEEDED: to better understand why and how the vaccine regimen reduced the risk of HIV infection to approach the mechanisms of protection to revise/define the endpoints of efficacy / Important implications for future HIV vaccine design and testing

19 Re-thinking future strategies for a suboptimal HIV-1 vaccine To consider bridging innate and adaptive immunity To elicit long lasting memory To target both: HIV antigens implicated in Infection and replication Broad & potent: - NAb responses (stabilized env trimers) - CTL response (Gag ) +/= HIV antigens implicated in cell to cell transmission and early abnormal pathogenic signals Which pathogenic determinant(env, nef )??? A highly efficient combined vaccine candidate targeting both the infection and the very early pathogenic signals in effector sites (including mucosa)

20 No Dogma New technologies, innovative and high-risk concepts, integrating basic and clinical science New vaccine discovery