Update on HIV Cure Research Robert F Siliciano

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

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

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

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 • 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, TLR 7 agonist) † Slide 4 of 50

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

Slide 6 of 50 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

Slide 7 of 50 Time to rebound Miss. Boston baby pt. A pt. B Log reduction in latent reservoir 6 5 4 Berlin pt. Chun et al. 3 2 1 1 wk 1 mo 3 mo 1 yr 10 yr Lifetime Time to rebound Hill et al, PNAS 2014

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