1. Robert F. Siliciano, MD, PhD Professor of Medicine The Johns Hopkins University School of Medicine Baltimore, Maryland Update on HIV Cure Research FORMATTED: 11/17/15 New Orleans, Louisiana: December 15-17, 2015

2. Slide 2 of 50 Slow decay of the reservoir Siliciano et al., Nature Med., 2003 Crook et al, JID 2015 t 1/2 = 43 months t 1/2 = 44 months

3. Slide 3 of 50 Approaches to HIV cure Gene Rx Prevent reactivation † Induce elite control TCR pathway agonists LRAs (HDACi) † † † Shock and kill

4. Slide 4 of 50 Current status of LRA trials TCR pathway agonists LRAs (HDACi) † † † Numerous LRAs identified in studies with transformed cell lines and primary T cell model systems Few shown to work ex vivo with cells from patients In clinical trials, no reduction in the reservoir yet demonstrated Some evidence for slight transient increases in plasma HIV RNA after LRA treatment (romidepsin, panobinostat, TLR7 agonist) In clinical trials, evidence for increases in cell-associated HIV RNA (Archin et al.)

5. Slide 5 of 50 Assays for latent HIV TCR agonist Viral outgrowth assay (VOA) DNA PCR PCR for proviral DNA Measure intracellular HIV RNA Induction of HIV RNA TCR agonist Measure virion release Induction of virion production TCR agonist

6. Slide 6 of 50 Take home points DNA PCR assays widely used for reservoir analysis mainly defect grossly defective proviruses The quantitative viral outgrowth assay remains the best available assay for the latent reservoir, but better assays are urgently needed. There is no clinical assay for the latent reservoir Other approaches: transient blips following LRA administration, time to rebound after ART interruption

7. Slide 7 of 50 Time to rebound Hill et al, PNAS 2014 Time to rebound Log reduction in latent reservoir 1 wk1 mo10 yr1 yr3 moLifetime 6 3 1 2 5 4 Berlin pt. Boston pt. B Boston pt. A Chun et al. Miss. baby

8. Slide 8 of 50 Time Post Infection (weeks)(years) 1,000,000 100,000 10,000 1000 100 Plasma HIV RNA (copies/ml) cART Therapeutic vaccination cLRAs What will cure look like?