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Treatments to modulate HIV reservoirs: A virological and immunological cross-talk

Prospects for Eradication: Determinants of Viral Reservoirs. Treatments to modulate HIV reservoirs: A virological and immunological cross-talk. Jean-Pierre Routy M.D. McGill University Montreal. HIV reservoirs. Viral definition:

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Treatments to modulate HIV reservoirs: A virological and immunological cross-talk

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  1. Prospects for Eradication: • Determinants of Viral Reservoirs Treatments to modulate HIV reservoirs:A virological and immunological cross-talk Jean-Pierre Routy M.D. McGill University Montreal

  2. HIV reservoirs • Viral definition: • The persistence of transcriptionally silent but replication-competent HIV, in the presence of HAART • Cellular definition: • Latently-infected resting memory cells harboring an integrated form of the viral genome that lacks the ability to produce viral proteins, in the presence of HAART • Reservoir of latently infected cells: • Resting memory CD4+ T cells • Monocyte/Macrophage lineage • Yet unidentified source: Brennan et al J virol 2009;June 2009 • Anatomic reservoir: CNS • Stability of such reservoir after years on HAART Strategies are needed to decrease and ultimately eradicate latently infected cells

  3. Proposed mechanisms for HIV reservoir persistence • Viral model: • Low levels of ongoing viral replication could lead to de novo infection of memory cells • Continuous replenishment of the reservoir • Provirus has to become transcriptionally active • HAART not fully potent: • Anatomic reservoir (CNS)? • Cellular model: • Infected monocytes/macrophages • Intrinsic stability of latently infected CD4 cells (survival) • Central memory CD4 cells survive for years • Pro-survival pathways are triggered (transcriptional factor FOXO3a) • van Grevenynghe et al. Nat Med. 2008; 14:266 • Cellular proliferation depends on: • Antigen-induced (TCR) • Cytokine-induced (homeostatic)

  4. Virologic model in 2009 • Recent data no longer support this model: • Reservoir sizes are established before therapy • Absence of genetic evolution in viral reservoir • Presence of a stable long-lived cellular reservoir • Ultrasensitve PCR: 1 copy/mL. Palmer S et al. PNAS 2008;105:3879 • Failure of treatment intensification: • Dinoso JB et al. PNAS 2009;106:9403 • Absence of anti-integrase effect (Raltegravir) on reservoir: • Sedaghat A et al. Antiviral therapy 2009; 14:263 • Ghandi et al. Raltegravir Intensification does not reduce low-level residual viremia. ACTG A5244

  5. Cellular model in 2009 • Memory CD4 cells are phenotypically and functionally heterogeneous: • Central Memory: Self renewal, persistence • CD45RA-, CCR7+, CD27+ • Transitional Memory: • CD45RA-, CCR7-, CD27+ • Effector Memory: Immediate effector function, short term survival: • CD45 RA-, CCR7-, CD27- • Late differentiated Memory: • CD45 RA+, CCR7-, CD27-

  6. CD4 cell depletion drives the reservoir size Chaumont et al. Nat Med June 2009

  7. CD4/CD8 ratio and duration of viremia drive the reservoir size Chaumont et al. Nat Med June 2009

  8. CD4 cells drive the size and the location of the HIV reservoir Transitory and effector memory Central memory Chaumont et al. Nat Med June 2009

  9. CD4 proliferation and immune activation drive the size and location of the HIV reservoir Ki67: Proliferation PD-1: T cell Activation Low Low Chaumont et al. Nat Med June 2009

  10. Central and transitional memory CD4 cells are driven by different mechanisms • Reservoir of patients with moderate CD4 recovery (< 500) consists mainly of transitory memory CD4 cells: • Immune activation and proliferation • Homeostatic proliferation (IL-7) • Reservoir of patients with adequate CD4 recovery ( > 500) consists mainly of central memory CD4 cells: • Low-level antigen driven proliferation (TCR) • Intrinsic T-cell survival (FOXO3a): Stem cell-like

  11. Proliferation index CML cells Akt phosphorylates FOXO3a to prevent apoptosis in CML ? TCM cells resemble chronic myeloid leukemia (CML) stem cells treated with Imatinib (Gleevec) – a tyrosine kinase inhibitor Kikuchi S et al. Cancer Science 2007; 98:1949Hui et al. Mol. and Cell. Biology 2008; 28:5886

  12. Persistence of reservoirs • Not due to lack of HAART potency • Driven by: • Immune activation and T cell proliferation • T cell survival • Treatments to modulate HIV reservoirs should be based on: • HIV latency • T cell dynamics

  13. Cons: CD4 memory cells are rare and do not contribute to pathogenesis HAART has improved and is less toxic Failure of initial attempt with HAART and IL-2 Risky intervention Priority for: Increasing HIV screening Early HAART initiation to decrease AIDS and non-AIDS events Pros: Lifelong adherence to therapy Unknown effects of long-term treatment Stigmatization due to HIV will last for life If we never try we will never succeed The “Berlin patient” Why treat the HIV reservoir?

  14. Long-term Control of HIV by CCR5Delta32/Delta32 Stem Cell Transplantation Atripla Monocyte and CNS reservoirs not targeted 2 transplantations for AML Hutter G et al NEJM 2009; 360: 692

  15. Reducing the HIV reservoir:Treatment objectives • A stepwise approach: • Reducing the HIV reservoir by: • Increasing CD4 recovery (central vs. effector CD4 memory) • Reducing immune activation • … should contribute to reducing non-AIDS events (inflammation) • ART-free remission: • No evidence of disease or symptoms • Cure: • No evidence of disease or symptoms • Eliminating every functional virion • Eliminating every infected cell

  16. A risk/benefit approach is necessary to conduct clinical research on the reservoir • Animal model: • Monkey model: Dinoso et al. J Virol July 2009 • Treatment during primary HIV infection: • CCR5 inhibitor, anti-integrase, IL-7 • Immunoreconstitution strategy: • Recovery of CD4 and CTL function • HIV-specific targeted therapy: • Anti-HIV latency strategies with HAART alone or associated with: • Immuno-reconstitution therapy • Therapeutic vaccine • Non-HIV specific therapy: • Cytotoxic approach: lymphoid with or without myeloablation

  17. IL-7: potential anti-latency and Immunoreconstitution therapy • Interleukin-7: • Inducing in vitro HIV expression without T cell activation: Archin et al Curr Opin HIV AIDS 2006;1:134 • Increasing naïve and central memory T cells: Levy et al J Clin Invest 2009;119:997 • Enhancing ex vivo CTL function: Sereti et al. Blood 2009; 113: 6304 • Early immune gut effect in monkeys: Nascimbeni et al Blood 2009; 113: 6112 • Alone or in combination with: • Therapeutic vaccine: • in mice with cancers. Pellegrini et al Nat Med 2009; 15: 528 • Monoclonal antibody with immunotoxin or intelligent radiotherapy

  18. IL-7 therapy:Mobilization of HIV (bleep) and HIV-specific T cells VL IL-7 Frequency of Gag-specific CD4+ T cells IFN-g IL-2 Percentages Y. Lévy et al, JCI 2009

  19. Strategies to enhance CTL function • Enhancing CTL (CD8) function • Dendritic cell therapy to increase antigen (HIV) presentation to CTL • Argos Therapeutics, CTN # 239 • TRF6 and fatty acid metabolism modulator: • Metformin and anti-cancer therapeutic vaccine in mice • Pearce et al. Nature June 2009 • Enhancing CTL function by modulating exhaustion: • CTLA 4: Kaufmann et al. J Immunol 2009;182: 5891 • IL-21 pathway: Frolick A et al. Science 2009; 324: 1576 • IL-10 pathway: Brokman MA et al. Blood 2009; 114:346 • Program death-1 (PD-1): Trautmann et al. Nat Med. 2006; 12:1198, Said et al. MOAA205, IAS 2009

  20. Enhancing CTL function by modulation of PD-1 pathway • PD-1 pathway: • Highly expressed on specific anti-HIV CD8 cells • Enhanced expression also on non-specific T cells • PD-1high CD4 cells harbor larger HIV reservoir • Anti-PD-1 antibody: • Enhanced ex vivo CTL function • Ongoing studies blocking PD-1 pathway: • Cancer patients: Berger et al 2008; 14: 3044 • HCV-infected patients: Nakamoto PloS Pathog 2009; Fev 27 • Auto-immunity: Reynoso et al J Immunol 2009; 182: 2102

  21. MicroRNAs and HIV latency

  22. HIV-specific strategy:“Shock and kill" • Hypothesis proposed by D. H. Hamer Curr HIV Res2004, 2:99-111 • Consist of 2 treatment phases: • "shock" phase: • Drugs which can reactivate HIV from latency in combination with ART to block viral spread, without increasing T cell activation • "kill" phase (cell destruction): • Natural means: immune response, viral cytopathogenicity • Drugs which induce cell death: Monoclonal antibodies, immunotoxin, radio-labeled antibodies • “Shock" phase: 2 classes of drugs • Histone deacetylase inhibitors (HDACIs) • NFKB-independent activators

  23. “Shock and kill" strategies: Histone deacetylase inhibitors • To induce HIV activation: • Pilot studies with valproic acid: • Yes and no: Lehrman and Margolis al. Lancet 2005; 366: 549 • No: Siliciano et al. JID 2007;195: 833 • Randomized controlled study: CTN # 205 • Deacetylase inhibitor and Prostratin: • Synergistic effect in vitro • Reuse et al. Plos One 2009;4:6093 • Class/isoform-selective HDACIs: In vitro • Associated with glutathione-synthesis inhibitor (BSO) • Savarini et al. Retroviral 2009; 6:52 • Followed by expected cell killing: • CTL and or viral killing?

  24. “Shock and kill" strategies: NFKB independent HIV activator • HIV LTR integrates the function of a multitude of transcription factors • NFKB-dependent: • Cell activation and proliferation • NFKB-independent: • Transcriptor factor Δ VII Ets-1: in vitro • Induces transcription from the HIV TLR leading to HIV production without inducing T cell activation Yang et al. PNAS 2009;106: 6321

  25. Non-HIV specific cell strategies for memory CD4 cells • Central memory CD4 cells: • Direct cell destruction: • Transitory blockade of immune stem cell specific receptor • siRNA for transcription factors (FOXO3a) • Transitory and effector memory CD4 cells: • Immune activation modulators: • Microbial translocation: Germ modifiers • TLRs modifiers: Chloroquine, CTN # 246 • IRF-7 modifiers • Anti-homeostasis factors: • Anti IL-7: Chomont et al. Nat Med July 2009

  26. Patients with malignancy: “Berlin’s patient-like therapy” • Objectives: • Myelo and T cell ablation with cytotoxic agents • Followed by repopulation of the immune system with HIV resistant cells • Important limitations: • CCR5 homozygosity: 3% of human population • Stem cell registries not assessing CCR5 status • Allo stem cell transplant: • “Graft versus Host effect”

  27. Strategies limited to patients with malignancy: “Berlin’s patient-like therapy” • New stem cell strategies: • Resistance-conferring genes into stem cells before transplantation to induce CCR5 defective receptor • Once-in-a-lifetime treatment • Autologous source; Zinc finger nucleases: • Perez et al. Nat Biotechnol. 2008; 26:808 • Clinical stem cell therapy in AIDS-related lymphoma: • Von Laer et al. J Gene Med 2006;8:658 • Autologous stem cell transplant • Ex vivo infected cell purging: • Phototherapy for activated T cells • Anti-CCR5 or other cell entry inhibitor • Direct in vivo gene transfer without prior cytoreductive therapy to achieve a sustained antiviral effect

  28. Conclusion • Likely no ongoing viral replication with HAART • Strategy could include mono or combination therapy with HAART • Early HAART represents the easiest intervention to control reservoir size (CD4 nadir effect) • Ethical considerations: • Risk/benefit to participate in therapeutic trials – a 4-step approach: • Primary HIV infection • Immunoreconstitution • HIV-specific strategies • Non-HIV specific strategies • Tissue sampling: • Leukopheresis, lymph node and gut biopsies • New commitment: • Infrastructure for translational research • International collaboration • IAS initiative

  29. Université de Montréal: Nicolas Chomont Mohamed El Far Lydie Trautmann Francesco Procopio Bader Yassine-Diab Genevieve Boucher Petronela Ancuta Cécile Tremblay Elias Haddad Rafick Sekaly Université McGill: Rachid Boulassel Richard Lalonde Marina Klein Norbert Gilmore Mark Wainberg CTN: Joel Singer Jacquie Sas Abbott Canada: Nabil Ackad Argos therapeutics: Charles Nicolette Cytheris: Michel Morre Thérèse Croughs Acknowledgement

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