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DEVELOP AND TEST STRATEGIES TO ENHANCE THE CAPACITY OF THE HOST IMMUNE RESPONSE TO CONTROL ACTIVE VIRUS REPLICATION Giuseppe Pantaleo, M.D. Professor of.

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Presentation on theme: "DEVELOP AND TEST STRATEGIES TO ENHANCE THE CAPACITY OF THE HOST IMMUNE RESPONSE TO CONTROL ACTIVE VIRUS REPLICATION Giuseppe Pantaleo, M.D. Professor of."— Presentation transcript:

1 DEVELOP AND TEST STRATEGIES TO ENHANCE THE CAPACITY OF THE HOST IMMUNE RESPONSE TO CONTROL ACTIVE VIRUS REPLICATION Giuseppe Pantaleo, M.D. Professor of Medicine Head, Division of Immunology and Allergy Executive Director, Swiss Vaccine Research Institute Lausanne University Hospital, Lausanne, Switzerland

2 HIV Replication Cycle and Sites of Drug Activity AZT (Zidovudine-Retrovir) ddl (Didanosine-Videx) ddC (Zalcitabine-Hivid) d4T (Stavudine-Zerit) 3TC (Lamivudine-Epivir) ABC (Abacavir-Ziagen) FTC (Emtricitabine, Emtriva) Capsid proteins and viral RNA Protease Nucleus Integrase Reverse Transcriptase NRTIs Tenofovir DF (Viread) nTRI Efavirenz (Sustiva) Delavirdine (Rescriptor) Nevirapine (Viramune) Etravirine (Intelense) NNRTIs Cellular DNA HIV Virons Indinavir (Crixivan) Ritonavir (Norvir) Saquinavir (Fortovase) Nelfinavir (Viracept) Lopinavir/ritonavir (Kaletra) Atazanavir (Reyataz) Fos Amprenavir (Aptivus) Darunavir (Prezista) Protease Inhibitors CD4 Receptor Fusion Inhibitor T-20 (enfuvirtide, Fuzeon) New HIV Particles CCR5 Antagonist Maraviroc (Celsentri) Integrase Inhibitor Raltegravir (Isentress) Unintegrated double stranded Viral DNA Viral RNA gag pol polyprotein Viral mRNA Integrated Viral DNA AttachmentUncoating Reverse Transcription IntegrationTranscriptionTranslation Assembly and Release

3 Why Does HIV Persist In Infected Individuals? Two Main Hypotheses Latent HIV Reservoir Size: cells Half life memory CD4 T cells: 43 months Estimated time for eradication: ~70 years under full virus suppression by ART Not susceptible to ART Not susceptible to the immune system Residual HIV Replication Covert cellular reservoir Priveleged anatomic compartment Resistant to HIV cytopathic effect Poorly accessible to cytotoxic CD8 T cells Minimal virus spreading Replenishment of the latent cellular reservoir T CM /T TM CD4 T cells CD4 T cells? Macrophages? DCs?

4 Immunological Measures Associated with Control of HIV Replication - I Functional profile Proliferation capacity (Migueles et al. Nat Immunol 2002, Zimmerli, PNAS, 2005; Day, J Virol, 2007) Polyfunctional cytokines profile (Pantaleo and Koup, Nat Med 2004, Harari et al., Blood 2004; Harari et al., J Immunol 2004, Betts et al., Blood, 2006) Cytotoxic profile Perforin/GrmB expression (Hersperger, PLoS Path, 2010; Migueles et al., Immunity 2008) Inhibition of virus replication (Freel et al., J Virol, 2010; Yang, JID, 2012 TCR avidity (Almeida et al., J Exp Med, 2008) TCR clonotypes and protective role of HLA class I molecules (Chen et al. Nat Immunol, 2012) Lack of exhaustion markers (Day, Nature, 2006; Trautmann, Nat Med, 2006)

5 Immunological Measures Associated with Control of HIV Replication - II Epitopes targeted More Gag- and fewer Env-epitopes (Kiepiela, Nature, 2006) Conserved among strains (Turnbull, J Immunol, 2006) Mutations having a fitness cost (Martinez-Picardo, J Virol, 2006) Immune Activation (lack of immune activation) (Many, Many Investigators) Genetic Factors Long-term nonprogressors (LTNP) and Elite controllers (EC): spontaneous control of HIV-1 replication and preservation of high CD4 T-cell counts in the absence of ART HLA-B*57, HLA-B*27 and HLA-B*5801 genotypes are associated with viral control (Carrington M, Annu Rev Immunol 2003) Genome-wide association studies indicate that: The HLA-viral peptide interaction is the main determinant of HIV-1 control (Pereyra F, Science 2010) Specific amino acids in the HLA-B peptide-binding groove are important in HIV-1 control (The international HIV controllers study, Science 2010)

6 Immunological Measures Associated with Control of HIV Replication Based on the immunological measures associated with control of HIV replication, the immunological interventions should : a) induce recovery of proliferation capacity of CD4 and CD8 T-cells b) induce polyfunctional T-cell responses c) reduce immune activation d) reduce T-cell exhaustion e) induce predominantly CD8 T-cells specific to Gag epitopes f) induce protective TCR clonotypes

7 Immunological Strategies to Modify the Host Immune Response Vaccination Cytokines Blockade of regulatory receptors Inhibitors of chronic immune activation

8 Immunological Strategies to Modify the Host Immune Response: Vaccines Therapeutic vaccine clinical trials performed in the last 15 years: Number of clinical trials: n = 29 Number of subjects enrolled: n = 4376 (3000 in one trial) Type of vaccine: recombinant proteins/peptides (used alone): 5 trials (n=460 subjects) altered/killed HIV: 1 trial (n = 3000 subjects) DNA-based vaccines: 5 trials (n = 121 subjects) Viral vector-based vaccines (used alone): 14 trials (ALVAC canarypox vector used in 8 trials, MVA poxvirus vector in 1 trial, NYVAC poxvirus vector in 1 trial, Fowlpox vector in 1 trial, Ad5 vector in 1 trial) ( n = 698 subjects) Dendritic cell-based vaccines: 4 trials (n = 97 subjects)

9 Immunological Strategies to Modify the Host Immune Response: Vaccines Therapeutic vaccine clinical trials performed in the last 15 years: Number of clinical trials: n = 29 Number of subjects enrolled: n = 4376 (3000 in one trial) Clinical efficacy: effect on viral load (HIV RNA copies/ml in plasma) 9 clinical trials: no therapeutic efficacy 6 clinical trials: therapeutic efficacy not measured 1 clinical trial (ongoing) 13 clinical trials: modest therapeutic efficacy measured (delayed viral load rebound in 5 trials, prolongation ART free time in 4 trials, 0.5 log reduction in plasma viremia in 3 trials and 0.26 reduction in plasma viremia in 1 trial)

10 Immunological Strategies To Modify The Host Immune Response: Cytokines Clinical clinical trials performed in the last 15 years: Number of clinical trials: n = 4 Number of subjects enrolled: n = 6007 (5806 in 1 trial) Type of cytokine (IL-2 in 3 trials and IL-7 in 1 trial) Clinical efficacy: effect on viral load (HIV RNA copies/ml in plasma) 2 clinical trials: no therapeutic efficacy 1 clinical trial: therapeutic efficacy not measured 1 clinical trial: modest therapeutic efficacy measured (prolongation ART free time)

11 Immunological Strategies to Modify the Host Immune Response What went wrong ? Skepticism in the field Limited understanding of the immune correlates of protection from HIV disease when most of these studies were performed The large majority of the studies were not appropriately powered to measure clinical efficacy Challenges in the assessment of the HIV latent cell reservoir Limited resources Mono therapy approach

12 Combination Strategies To Purge The HIV Reservoir Latent Reservoir T CM /T TM CD4 cells Reactivation of replication HDAC Inhibitors, SAHA, Prostratin, Bryostatin 1, 5-azathidine, anti-PD-1 Therapeutic vaccine, anti-PD-1, Cytokines (IL- 2, IL-7), Inhibitors of immune activation Potentiation of immune response APOPTOSIS Killing by effector CD8 T cells HIV cytopathic effect Potentiation of immune response Covert Cellular Reservoir with Residual Replication APOPTOSIS Selective targeting Antibody coupled with toxins

13 Therapeutic vaccine programme From POC to Clinical and surrogate end points Accurate quantification of the therapeutic effect, i.e. immunogenicity (broad polyepitopic and polyfunctional T cell responses) Biomarkers associated with residual replication (markers of Immune activation and inflammation) reduction of the latent cell reservoir over time (decrease of viral DNA levels in blood and gut; integrated/non integrated DNA; frequency of latent replicating cells) Development of mathematical model to monitor the immune responses (integrated analysis) durability of the therapeutic effect over time (effect of repeated boosts) prediction (correlates)

14 04812 HAART plus DC (LPS-IFN)-HIV lipo 5 vaccine 19 pts Interrupt HAART weeks 24 Primary endpoint Safety 1622 Vaccinations 48 Secondary endpoint Immunogenicity * Follow up Immune status Viral status END OF STUDY DALIA 1 trial: outline HIV+, CD4>500 cells/ l Nadir > 300 cells/ l HIV RNA < 50 cp/ml c-ART > 12 months Y. Lévy, R. Thiébaut, G. Chène, J. Banchereau, K.Palucka CROI 2012, Seattle, # G-109 * Elispot IFN-,ICS, Luminex, transcriptomic (blood, cells)

15 Changes in plasma HIV RNA viral loads Changes in plasma HIV RNA viral loads Weeks

16 CD4 CD8 PRE-VACCINATIONPOST-VACCINATION IL-2 IFN Vaccination with DCs leads to expansion of LIPO-5 mix-specific T cells in the blood D1-11 Y. Levy et al CROI 2012

17 Luminex responses (IFN- ) Y. Levy et al CROI 2012

18 DALIA (Laura Richert) L. Richert et al, IAS 2012 Abs THPE097

19 h-IFNg, IL-10 ICS CD3, CD8 HIV+ Apher PBMC IL-2 (day 2) day 7 Restim Supernatant for LUMINEX 48h IL-2 IL-17 IL-21 TNF IP10 IL-13 Il-1 IL-10 Aphr1 Profile of Cytokine Induced by HIV Gag Peptides by Luminex + Monica Montes, Sandy Zurawski (BIIR) + Sophie Hue (MIC)

20 DALIA J. Skinner, Y.Levy, R. Thiébaut, J. Banchereau, D. Chaussabel AIDS Vaccine 2011, Bangkok

21 An inverse correlation was found between the maximum observed VL and: % of polyfunctional CD4+ (r=-0.63, FDR=.007); production of IL-2 (r=-0.67, FDR=.006); IFN-γ (r=-0.58, FDR=.01); IL-21 (r=-0.66, FDR=0.006) and IL-13 (r=-0.78, FDR=.001). Principal Component Analysis: Correlation immunogenicity and Virological markers L. Richert et al, IAS 2012 Abs THPE097

22 Collaboration for HIV/AIDS Immunological Therapy (CHAIT) Partners:Swiss Vaccine Research Institute/Lausanne University Hospital Vaccine Research Institute, France Boheringer Ingelheim FIT Biotech GSK Biologicals Sanofi Pasteur ViiV Healthcare

23 Scope and Objectives of the CHAIT Initiative Establishment of a task force for the development of immunological therapeutic interventions to achieve Functional HIV Cure and with the ultimate objective of HIV eradication. Engagement of multidisciplinary expertise from academia and industry. A public-private partnership initiative is necessary for developing an innovative scientific roadmap for the clinical development of combined immunological therapeutic interventions to complement ART. Added value and objectives: to identify scientific priorities to develop new concepts to bring into clinical development to engage a dialogue with Regulatory Agencies to define new criteria of response to therapy to advocate for ear-marked funding at the level of international funding agencies and to seek secured funding for long-term clinical studies.


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