Update on HIV Cure Research

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

2. Slow decay of the reservoir t1/2 = 44 months Siliciano et al., Nature Med., 2003 t1/2 = 43 months Crook et al, JID 2015

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

4. Current status of LRA trials • 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 TCR pathway agonists † • In clinical trials, no reduction in the reservoir yet demonstrated † LRAs (HDACi) • In clinical trials, evidence for increases in cell-associated HIV RNA (Archin et al.) † • Some evidence for slight transient increases in plasma HIV RNA after LRA treatment (romidepsin, panobinostat, TLR7 agonist)

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

6. Take home points • There is no clinical assay for the latent reservoir • 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. • Other approaches: transient blips following LRA administration, time to rebound after ART interruption

7. Time to rebound Miss. baby 6 Boston pt. A Boston pt. B 5 Berlin pt. 4 Chun et al. Log reduction in latent reservoir 3 2 1 1 wk 1 mo 3 mo 1 yr 10 yr Lifetime Time to rebound Hill et al, PNAS 2014

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