5/11/2017. HIV Cure Research Questions and a Few Answers

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1 HIV Cure Research Questions and a Few Answers Steven G. Deeks, MD Professor of Medicine University of California San Francisco San Francisco, California FORMATTED: 04/13/17 Financial Relationships With Commercial Entities Dr Deeks has served as a consultant for EMD Serono, Inc, on the scientific advisory board for BryoLogyx, Inc, and has received research support from Merck, ViiV Healthcare, and Gilead Sciences, Inc. (Updated 04/13/17) Slide 2 of 42 Learning Objectives After attending this presentation, learners will be able to: Describe where HIV resides during long-term antiretroviral therapy Outline the major causes of HIV persistence during therapy Describe the barriers to measuring the HIV reservoir Describe viable pathways towards a cure for HIV infection Slide 3 of 42 1

2 HIV Cure: Lots of questions and a few answers Slide 4 of 42 How much is there? How stable is the reservoir? Where does it reside? Can it be measured? Can latency be prevented? Can latency be reversed? Can the virus be controlled? How much should it cost? What do we know about the size and stability of the reservoir? Slide 5 of 42 Although ART reduces viremia > 6 to 7 log 10 some virus persists indefinitely (0.1-3 copies RNA/mL) Source of the viremia is not known but it is not from an actively replicating population Slide 6 of 42 Log vrna Copies/ml Start Treatment Weeks Post Infection 2

3 The vast majority of HIV resides in the lymphoid organs, most of it assumed to be in CD4+ T cells, but the macrophage-rich tissues are understudied? (HIV+ cells/gram tissue) (kidney) 10 6 (large bowel) (LN) (spleen) 10 5 (small bowel) Courtesy of Tim Schacker The active reservoir in nodes declines slowly over time and appears to be correlated with the level of lymphoid inflammation (germinal centers) Slide 9 of 42 What do we know about the types of CD4+ T cells that harbor HIV during ART? Slide 9 of 42 3

4 Modest enrichment of HIV has been reported in certain CD4+ T cell subsets Activated/proliferating HLA-DR, PD-1, LAG-3, CTLA-4, TIGIT T follicular helper cells (nodes) Migrating: CCR6, 4 β7 Effector cells Slide 10 of 42 1 Chomont, Nat Med Murray JV Hatano JID Cockerham PLoS ONE Wang JID Chun JCI Riddler (unpublished). 8 Lewin (unpublished). 9 Hatano JID Frometin (unpublished) HIV enriched (100 to 1000 fold) in CD32a-expressing CD4 + T cells Most (> 50%) of reservoir may be in these cells, even though they are rare (~1% of CD4+ T cell population) Slide 12 of 42 How does HIV persist indefinitely? Slide 12 of 42 4

5 Does HIV replicate (or spread) during ART? No evolution Pre-ART virus rebounds No failure Early evolution Low ART, CTL in LN Intensification Slide 13 of 42 Cell proliferation maintains the reservoir during ART Up to 50% of infected cell population (blood) is clonal in nature Integration sites enriched for genes associated with cell growth/cancer Slide 14 of 42 B cell follicles: a relative immune-privileged sanctuary for HIV-infected Tfh T cells Slide 15 of 42 Fukazawa et al., Nature Med 2015; Banga et al., Nature Med 2016; Leong et al., Nature Immunol

6 Can the reservoir be measured? Slide 16 of 42 HIV Reservoir Vast majority of genomes are defective Population of replication-competent HIV that persists during ART and ignites new rounds of replication when ART is stopped Rare, tissue-based, may be impossible to directly measure Slide 17 of 42 Slide 18 of 42 Virus in blood: often clonal and archival Virus in LN: enriched in the follicles (Tfh cells) and actively replicating Blood and tissue reservoirs are not the same 6

7 Cancer: rare tissue based cells that are similar to healthy cells and hard to detect Sensitive tracers that detect cancer (or HIV) being developed Slide 19 of 42 When is the reservoir established? Slide 20 of 42 At about the time HIV RNA becomes detectable, the reservoir size begins to increase dramatically, with an apparent 100-fold increase over the next two weeks Reservoir largely established by week 4 of infection Slide 21 of 42 7

8 Very early ART reduces the reservoir but is not curative N=8; ART in Fiebig I for >96 weeks; VL<50 c/ml; CD4>400 cells/ul Slide 22 of 42 Ananworanich J et al., CROI 2017, Seattle, WA ART (PrEP) during Fiebig 0 Stage 20 adults (and one child) who started therapy early (but not in hyperacute stage), remained on therapy for years, and had no rebound after stopping therapy Low reservoir size, low T cell activation and strong immune responses Slide 24 of 42 8

9 What will a cure have to look like to have a global impact? Slide 25 of 42 Efficacy: aviremia in absence of therapy > 2 years; early failure is tolerable, late failures must be rare Product: oral/parental; administered for limited period of time (e.g., 6 months); specialized (tertiary) care not required Target Population: effective ART initiated at any stage and in all populations (gender, subtype) Long-term safety: comparable to ART, transmission risk negligible Cost: < $1400 (RLS) Slide 26 of 42 How will we cure HIV infection? Slide 27 of 42 9

10 Viable pathways towards a durable remission/cure Slide 28 of 42 Gene and cell-based therapy Proof of concept: Berlin Patient Multiple feasible pathways, none yet scalable Early ART Sterilizing cure not possible (Mississippi case, Fiebig 0 case) Post-treatment control (VISCONTI) occurs rarely when ART is started early (not acute) Immunotherapy: remission (post-treatment control) Shock and kill: reservoir reduction How will we cure HIV infection? In absence of heroic interventions (e.g., gene therapy), it is likely that a remission will likely be easier to achieve than a complete cure Several viable combinatorial approaches are now moving towards proof-of-concept testing Slide 29 of 42 All models of durable SIV/HIV remission suggest that durable control of established infection will require (1) low disease burden, (2) low inflammation and (3) sustained T cell responses that are primed, reside in tissues, and target susceptible epitopes These same attributes apply to cancer immunotherapy Slide 30 of 42 10

11 Adjuvants TLR agonists Immunemodifying ICBs Anti-inflammatory Rx Sanctuary Disruption CD20 antibody Cytokines Vaccine CMV DNA/RNA Adeno/MVA HIV Remission Low Reservoir Early ART LRAs Slide 31 of 42 Therapeutic vaccines: Safe, generally immunogenic and associated with no benefit in most studies and modest benefit in some studies Trial Regimen Comment Author/Paper Slide 32 of 42 ACTG 5068 ALVAC (vcp1452) Intermitting interruptions but not vaccine Jacobson, JID associated with reduced VL 2006 ACTG 5024 ALVAC (vcp1452) + IL- 0.5 log VL reduction during ATI Kilby, JID ACTG 5097 Ad log10 Schooley, JID 2010 MANON-02 ALVAC-HIV No VL effect; activated CD4 cells may have Papagno, AIDS induced early failure 2011 Bionor p24 peptide mixture ATI: no VL effect at primary endpoint, mild Pollard, Lancet (Vacc-4x) benefit at later time points HIV 2014 ERAMUNE DNA prime/mva boost No effect (HIV DNA) Achenbach, 02 Lancet HIV 2015 GeneCure Replication-defective Reduced VL set-point (compared to historical Tung, Vaccine HIV with VZV fusion data) 2016 protein (HIVAX) GeoVax DNA prime/mva boost No apparent effect during ATI (uncontrolled) Thompson, (virus-like particles) PLoS ONE 16 ACTG 5281 Gag/Pol, Minimal CD4 effects, no CD8 effects, low dose Jacobson, Nef/Tat/Vif/Env and IL- IL-12 better than high dose IL-12 JAIDS plasmids (Profectus) BCN 02 ChAdV63.HIVconsv + 5/13 controlled (ATI) Mothe, CROI MVA.HIVconsv 17 Immunotherapy for HIV infection Two decades of largely failed approaches Weak immunogenicity Pre-existing immuno-dominant responses CTL escape Inflammation and counter-regulatory immunosuppression High virus burden Immune-privileged tissue sanctuaries Slide 33 of 42 11

12 Vaccine (Ad26/MVA primeboost) alone had minimal effect on reservoir Vaccine + TLR7 agonist (Gilead) reduces reservoir during ART and controls SIV post-art Slide 34 of 42 BCN02 Trial: HIV vaccine with latency reversal induces sustained HIV control in 5 individuals (8 individuals failed) Slide 35 of 42 Cancer immunotherapy is reshaping a fatal and progressive disease much as ART reshaped HIV Most therapies aim to enhance capacity of CD8+ T cells to recognize and clear rare tissue-based cells that reside in inflamed tissues Upregulation of checkpoint blockers (PD- 1, CTLA-4) Immunosuppressive cytokines (TGF-β, IL-10, IDO) Immunosuppressive immune cells (T-regs, MDSCs) Slide 36 of 42 12

13 How will we reduce the reservoir size to a level such that the immune system can conceivably control what is left? Slide 37 of 42 Shock and Kill Goals have shifted from complete eradication ( cure ), which is likely not possible, to reduction, which will be essential for immune control ( remission ) Slide 38 of 42 Slide 39 of 42 13

14 State of the ART: 2017 Location, size and stability of reservoir remains to be characterized Measuring total body replication-competent reservoir not possible Cellular reservoirs now being explored Mechanisms for persistence known: latency, poor CTL, cell proliferation The reservoir can be reduced with early ART and cell therapy but not with anything scalable It is possible to reverse latency (shock) but the impact on the reservoir is negligible and most approaches are toxic Therapeutic vaccines work in monkeys and perhaps humans Combination approaches will be needed and are now moving into the clinic (era of experimental medicine ) Slide 40 of 42 Acknowledgements Slide 41 of 42 HIV Cure Research Questions and a Few Answers Steven G. Deeks, MD Professor of Medicine University of California San Francisco San Francisco, California FORMATTED: 04/13/17 14