Interactive Workshop

“HIV Cure 101”:Strategies for Targeting and

Eradicating the HIV Reservoir

J. D. LifsonAIDS and Cancer Virus ProgramLeidos Biomedical Research, Inc.

Frederick National LaboratoryFrederick, MD, United States

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

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

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

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

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

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

• 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