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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

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http://www.nytimes.com/2011/11/29/health/ new-hope-of-a-cure-for- hiv.html?pagewanted=all&_r=0 http://www.advocate.com/news/2009/01/24/ aids-hero-martin-delaney-dies-california

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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