Interactive Workshop “HIV Cure 101”: Strategies for Targeting and Eradicating the HIV Reservoir...
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Interactive Workshop “HIV Cure 101”: Strategies for Targeting and Eradicating the HIV Reservoir J. D. Lifson AIDS and Cancer Virus Program Leidos Biomedical Research, Inc. Frederick National Laboratory Frederick, MD, United States
Interactive Workshop “HIV Cure 101”: Strategies for Targeting and Eradicating the HIV Reservoir J. D. Lifson AIDS and Cancer Virus Program Leidos Biomedical
Interactive Workshop HIV Cure 101: Strategies for Targeting and
Eradicating the HIV Reservoir J. D. Lifson AIDS and Cancer Virus
Program Leidos Biomedical Research, Inc. Frederick National
Laboratory Frederick, MD, United States
Definitions Reservoir: Virus that persists despite apparently
effective suppressive cART, and is capable of giving rise to
recrudescent infection if/when cART is stopped Cure (definitive
treatment beyond lifetime cART): Eradication: Elimination through
treatment of all virus capable of giving rise to recrudescent
infection if/when cART is stopped Functional Cure (sustained off
treatment remission): Not complete elimination of reservoir, but
reduction of reservoir to levels sufficiently low, with sufficient
host control, to limit/abrogate pathogenesis and minimize/eliminate
risk of transmission
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Strategy for Development of ART: Understand and Target
Vulnerable Steps in Viral Replication Cycle
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Parallel Approach for HIV Cure Understand underlying biology of
reservoir Identify potential vulnerable opportunities for
intervention (individual, combination) In vitro, ex vivo, and
animal model proof of concept studies with prototype interventions
Clinical evaluation as warranted Risk/benefit considerations
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Challenges for HIV Cure Reservoirs: Sources of persistent
residual virus on suppressive cART that can give rise to
recrudescent infection and progressive disease when cART is stopped
Residual virus replication (active reservoir) Long lived infected
cells Latent reservoirs Epigenetic and transcriptional mechanisms
of latency Anatomic and cell lineage compartments Pharmacological
or immunological sanctuary sites Must eliminate or control last
virus capable of recrudescence
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Approaches to HIV Cure: Mechanism Based and Empirical cART
intensification Transcriptional activators Epigenetic modulators
Immune modulators Cytokines Immune checkpoints Immune targeting
(require viral expression) mAbs Adoptive cell therapy (engineered
cells) Therapeutic vaccination Combinations
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CMV-vectored vaccines; highly unusual vaccine induced T cell
responses Viral control after i.r, i.vag., and i.v. challenge
Control established over disseminated infection, not just at portal
of entry Progressive clearance of virus over time, including from
tissue sites Functional cure and apparent eradication in protected
animals