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Steven G. Deeks, MDProfessor of Medicine
University of California San FranciscoSan Francisco, California
HIV Cure Research Questions and a Few Answers
FORMATTED: 04/13/17
Chicago, Illinois: May 10, 2017
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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)
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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
therapyDescribe the barriers to measuring the HIV reservoirDescribe viable pathways towards a cure for HIV
infection
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HIV Cure: Lots of questions and a few answers
• 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?
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What do we know about the size and stability of the “reservoir”?
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0 5 10 15 20 25 30 350
1
2
3
4
5
6
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8 36160
3625336348
3634936488
3654436661
Start Treatment
3635336166
Weeks Post Infection
Log
vRN
A C
opie
s/m
l
Although ART reduces viremia > 6 to 7 log10 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
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10104
103
105 (spleen)106 (large bowel)
105 (small bowel)106-7 (LN)
10 (kidney)
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
?
Courtesy of Tim Schacker
(HIV+ cells/gram tissue)
The “active” reservoir in nodes declines slowly over time and appears to be correlated with the level of lymphoid inflammation (germinal centers)
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What do we know about the types of CD4+ T cells that harbor HIV during ART?
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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
1Chomont, Nat Med 09. 2Murray JV 14. 3Hatano JID 12. 4Cockerham PLoS ONE 14. 5Wang JID 14. 6Chun JCI 05. 7Riddler (unpublished). 8Lewin (unpublished). 9Hatano JID 14. 10Frometin (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)
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How does HIV persist indefinitely?
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Does HIV replicate (or spread) during ART?
Early evolution Low ART, CTL
in LN Intensification
No evolution Pre-ART virus
rebounds No failure
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Up to 50% of infected cell population (blood) is clonal in nature
Integration sites enriched for genes associated with cell growth/cancer
Cell proliferation maintains the reservoir during ART
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B cell follicles: a relative immune-privileged sanctuary for HIV-infected Tfh T cells
Fukazawa et al., Nature Med 2015; Banga et al., Nature Med 2016; Leong et al., Nature Immunol 2016
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Can the reservoir be measured?
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HIV ReservoirVast 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
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Virus in blood: often clonal and archival
Virus in LN: enriched in the follicles (Tfhcells) and actively replicating
Blood and tissue reservoirs are not the same
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• Cancer: rare tissue based cells that are similar to healthy cells and hard to detect
• Sensitive tracers that detect cancer (or HIV) being developed
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When is the reservoir established?
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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
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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
Ananworanich J et al., CROI 2017, Seattle, WA
ART (PrEP) during “Fiebig 0” Stage
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• 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
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What will a cure have to look like to have a global impact?
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• 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)
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How will we cure HIV infection?
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Viable pathways towards a durable remission/cure
• 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
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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
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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
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HIV Remission
Vaccine
CMV
DNA/RNA
Adeno/MVA
Adjuvants
TLR agonists
Immune-modifying
ICBs
Anti-inflammatory Rx
Sanctuary Disruption
CD20 antibody
Cytokines
Low Reservoir
Early ART
LRAs
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Therapeutic vaccines: Safe, generally immunogenic and associated with no benefit in most studies and modest benefit in some studies
Trial Regimen Comment Author/Paper
ACTG 5068 ALVAC (vCP1452) Intermitting interruptions but not vaccine associated with reduced VL
Jacobson, JID 2006
ACTG 5024 ALVAC (vCP1452) + IL-1
0.5 log VL reduction during ATI Kilby, JID 2006
ACTG 5097 Ad5 0.24 log10 Schooley, JID 2010
MANON-02 ALVAC-HIV No VL effect; activated CD4 cells may have induced early failure
Papagno, AIDS 2011
Bionor p24 peptide mixture (Vacc-4x)
ATI: no VL effect at primary endpoint, mild benefit at later time points
Pollard, Lancet HIV 2014
ERAMUNE 02
DNA prime/MVA boost No effect (HIV DNA) Achenbach, Lancet HIV 2015
GeneCure Replication-defective HIV with VZV fusion protein (HIVAX)
Reduced VL set-point (compared to historical data)
Tung, Vaccine 2016
GeoVax DNA prime/MVA boost (virus-like particles)
No apparent effect during ATI (uncontrolled) Thompson, PLoS ONE 16
ACTG 5281 Gag/Pol, Nef/Tat/Vif/Env and IL-12 plasmids (Profectus)
Minimal CD4 effects, no CD8 effects, low dose IL-12 better than high dose IL-12
Jacobson, JAIDS 2016
BCN 02 ChAdV63.HIVconsv + MVA.HIVconsv
5/13 controlled (ATI) Mothe, CROI 17
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Immunotherapy for HIV infectionTwo 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
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Vaccine (Ad26/MVA prime-boost) alone had minimal effect on reservoir
Vaccine + TLR7 agonist (Gilead) reduces reservoir during ART and controls SIV post-ART
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BCN02 Trial: HIV vaccine with latency reversal induces sustained HIV control in 5 individuals (8 individuals failed)
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Cancer immunotherapy is reshaping a fatal and progressive disease much as ART reshaped HIVMost 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)
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How will we reduce the reservoir size to a level such that the immune system can conceivably control what is left?
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Shock and KillGoals have shifted from complete eradication (“cure”), which is likely not possible, to reduction, which will be essential for immune control (“remission”)
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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”)
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Acknowledgements
Steven G. Deeks, MDProfessor of Medicine
University of California San FranciscoSan Francisco, California
HIV Cure Research Questions and a Few Answers
FORMATTED: 04/13/17
Chicago, Illinois: May 10, 2017
Chicago, Illinois: May 10, 2017