1. Strategies for Targeting and Eradicating the HIV Reservoir
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

2.
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3. 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

4. Strategy for Development of ART:
Understand and Target Vulnerable Steps in Viral Replication Cycle

5. 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

6. 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

9. 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

12. 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