1. Are we most likely to cure HIV with gene therapy? Sharon R Lewin Director, Infectious Disease Unit, Alfred Hospital Professor, Department of Medicine, Monash University Co-head, Centre for Virology, Burnet Institute, Melbourne, Australia Amfar-IAS Satellite Meeting, 5 th IAS Conference, Rome

2. Gene therapy is scientifically flawed, high risk, will never get to the clinic

3. The problem: 1 in a million cells are latently infected

4. Nucleases chop up DNA – lets hope they get it 100% right! Naldini et al., Nature Genetics 2011; 12:301

5. Pharmacotherapy is rational, short term, toxicities that are mild and reversible, available now to test, scalable

6. Licensed drugs that also …..eliminate latently infected cells HDACi Vorinostat Yes Romidepsin Yes Panabinostat Entinostat Givinostat Belinostat 2 5-azacytidine Others (9) 1 Disulfiram Yes 1 Minocycline ` Yes Auranofin Yes Phase I Phase II Phase III LicensedLatency trials Methylation inhibitor Cytokine Anti-alcoholic Antibiotic Anti-rheumatic Interleukin-7 * Total number of trials listed on http://clinicaltrials.gov (July 2011) # Trials* 176 32 94 20 28 7 >26 52 20 Latent HIV activity Latency activators Immune modulators MDX-1106 Anti PD-1 + + + + + + + + + - + + + 9 Bryostatin PKC modulators + 22 Others Yes (1) +

7. Combination strategies enhance potency SAHA + Pro Viral RNA (copies/ml) 50000 0 20000 30000 40000 10000 NI VPA SAHA VPA + Pro Pro 60000 WHS 22 Pro = prostratin; VPA = valproic acid; SAHA = vorinostat Reuse et al., Plos One 2009 Latency activators (combination) Immune modulators +

8. New possibilities to enhance specificity AIDS 2009; 23(14):1799-806 Plos One 2011; 6: e18270

9. We need a cure that is scalable, deliverable and cheap http://www.afripol.org/africa-newspapers/3-africa/2-newshour-with-jim-lehrer-africa-coverage-pbs.html