Approaching a Cure Daniel R. Kuritzkes, MD

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1 Approaching a Cure Daniel R. Kuritzkes, MD Division of Infectious Diseases Brigham and Women s Hospital Harvard Medical School

2 Disclosures The speaker is a consultant and/or has received speaking honoraria and/or grant support from the following companies relevant to this talk: Bionor Gilead GlaxoSmithKline InnaVirVax Merck Kuritzkes IAS Cure Vancouver

3 Defining cure HIV eradication Elimination of all HIV from blood and tissue reservoirs Functional cure No detectable HIV in blood or tissues in absence of ART (but cannot disprove HIV persistence at inaccessible sites) Durable ART-free remission No plasma viremia or transmissible virus off ART (but detectable HIV might persist in cells, tissues)

4 Mechanisms of Persistence Kuritzkes IAS Cure Vancouver

5 B-T cell interactions are required for Tfh development and persistence Courtesy of R. Sekaly Kuritzkes IAS Cure Vancouver

6 Bruner et al CROI 2016, Boston, MA, February 22-25, 2016.

7 Expanded clones are grossly defective Bruner et al CROI 2016, Boston, MA, February 22-25, 2016.

8 Accumulation of defective proviruses Bruner et al CROI 2016, Boston, MA, February 22-25, 2016.

9 Conclusions Proviruses in individuals initiating ART during chronic HIV infection are overwhelmingly defective (<5% are intact) Defective proviruses are readily detected even even after a single round of infection Individuals initiating ART with 3 months of infection have a high percentage of defective proviruses, indicating accumulation early after infection Hypermutation more prominent in acute infection Expanded clones are readily detected and predominantly defective in patients who initiated ART during acute or chronic infection Bruner et al CROI 2016, Boston, MA, February 22-25, 2016.

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11 Impact of chemotherapy on the HIV reservoir Henrich et al CROI 2016, Boston, MA, February 22-25, 2016.

12 Change in CD4 T-cells after chemo Henrich et al CROI 2016, Boston, MA, February 22-25, 2016.

13 Distribution of proviral DNA in CD4+ T-cells Henrich et al CROI 2016, Boston, MA, February 22-25, 2016.

14 Conclusions Cytoreductive therapy may reduce HIV reservoirs in some patients manifesting as a constriction of HIV sequence diversity Response to EBV/CMV antigens may lead to olilgoclonal expansion of cells harboring HIV-1 DNA during immune reconstitution Tissue and sequence analysis will be critical to provide a more complete understanding of the impact of chemotherapy and other interventions on HIV persistence Henrich et al CROI 2016, Boston, MA, February 22-25, 2016.

15 Approaches to HIV cure Cell-based therapies Allogeneic transplantation Autologous transplantation of gene-edited cells Peripheral CD4+ T cells after gene editing Latency reversal HDAC inhibitors TLR agonists Immune-based interventions Immune check-point blocker inhibitors Therapeutic vaccines Broadly neutralizing antibodies

16 Partial successes Vorinostat Archin et al Nature 2012 Archin et al J Infect Dis 2014 Elliott et al PLoS Pathogens 2014 Panobinostat Rasumussen et al Lancet HIV 2014 Romidepsin Søgaard et al PLoS Pathogens 2015 Leth et al CROI 2016 Kuritzkes IAS Cure Vancouver

17 Whitney et al CROI 2016, Boston, MA, February 22-25, 2016.

18 TLR7 Agonists Induce Transient Plasma Viremia Whitney et al CROI 2016, Boston, MA, February 22-25, 2016.

19 Plasma SIV RNA rebound after stopping ART Whitney et al CROI 2016, Boston, MA, February 22-25, 2016.

20 Conclusions Repeated low doses of GS-986 and GS-9620 demonstrate: Minimal to no plasma IFN-α Induction of other cytokines/chemokines and immune activation Induction of transient plasma viremia Administration of up to 19 doses of TLR7 agonist was well-tolerated 2 of 9 treated monkeys remained aviremic for at least 3 months after stopping ART Clinical studies of GS-962- in HIV-infected participants on suppressive ART are underway

21 Safety, Immunologic and Virologic Activity of Anti-PD-L1 (BMS ) in HIV Participants on ART ACTG A5326: Phase 1, double-blind, placebocontrolled, ascending single-dose study Co-authors: Joseph J. Eron, Jr., Cynthia Gay, Ronald Bosch, Justin Ritz, Jason Hataye, Carey Hwang, Randall Tressler, Stephen Mason, Edward Acosta, Richard Koup and John Mellors Eron et al CROI 2016, Boston, MA, February 22-25, 2016.

22 PD-1/PD-L1 axis and immune exhaustion Courtesy G. Pantaleo

23 Hypotheses A5326 Single doses of anti-pd-l1 antibody (BMS ) in patients on suppressive cart will be safe and well-tolerated Blocking the PD-1/PD-L1 axis with anti-pd-l1 antibody will enhance HIV-1-specific immune responses Enhancement of HIV-1 specific immune responses will promote clearance of HIV-1 expressing cells and reduce persistent viremia Eron et al CROI 2016, Boston, MA, February 22-25, 2016.

24 Change in HIV gag-specific CD8+ T- cells (IFN-γ production) Eron et al CROI 2016, Boston, MA, February 22-25, 2016.

25 Change in HIV-1 cell-associated RNA to DNA ratio Eron et al CROI 2016, Boston, MA, February 22-25, 2016.

26 Summary Generally well-tolerated One serious adverse event consistent with autoimmunity Increase in HIV-1-sppecific CD8+ T-cell responses in 2 of 6 participants Corresponded to their ex vivo proliferative response to HIV- 1 gag peptides after exposure of pre-therapy samples to anti-pd-l1 Response rate similar to anti-tumor responses in humans and SIV control in rhesus macaques No clear impact on viremia, cell-associated HIV-1 RNA or proviral DNA Eron et al CROI 2016, Boston, MA, February 22-25, 2016.

27 ACTG A5340: the effect of VRC01 on viral kinetics after analytical treatment interruption Katherine J. Bar, Linda J. Harrison, Edgar T. Overton, Mark Bardsley, Michael Messer, Edmund Capparelli, Barney Graham, Richard A. Koup, James A. Hoxie, Pablo Tebas for the ACTG A5340 Team Bar et al CROI 2016, Boston, MA, February 22-25, 2016.

28 ACTG A5340: study design Bar et al CROI 2016, Boston, MA, February 22-25, 2016.

29 ACTG A5340: Viral Rebound Bar et al CROI 2016, Boston, MA, February 22-25, 2016.

30 ACTG A5340: Time to viral rebound Bar et al CROI 2016, Boston, MA, February 22-25, 2016.

31 ACTG A5340: Conclusions Passive administration of VRC01 Is safe and well-tolerated Modestly delays the return of viremia compared to historical controls Does not maintain viral suppression in the majority of participants Rebound virus analyses suggest VRC01 can restrict the clonality of rebounding virus and select pre-existent minority variants resistant to VRC01 Future studies testing the efficacy of combination bnabs, baseline susceptibility to neutralization, and in vivo mechanism of action are warranted Bar et al CROI 2016, Boston, MA, February 22-25, 2016.

32 Summary Better understanding of virologic and immunologic mechanisms of HIV persistence Quantifying the reservoir remains a challenge Stronger latency reversal agents are needed Treatment with immune modulators entails risk

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