1. Controversies in HIV Cure Research 18.3 0 Debate 1. Is there ongoing replication under HAART? Mario Stevenson and Frank Maldarelli Moderator: Steve Deeks 19.1 0 Debate 2. Will cell and animal models be informative in planning clinical trials for a cure (or will we only learn from doing the trials)? Alan Landay and Guido Silvestri Moderator: Rafick Sekaly 19.5 0 Debate 3. How are we most likely to cure HIV? Gene Therapy vs Pharmacology Sharon Lewin and Keith Jerome Moderator: Mark Harrington Debate 1. Is there ongoing replication under HAART? Mario Stevenson and Frank Maldarelli Moderator: Steve Deeks Debate 2. Will cell and animal models be informative in planning clinical trials for a cure (or will we only learn from doing the trials)? Alan Landay and Guido Silvestri Moderator: Rafick Sekaly Debate 3. How are we most likely to cure HIV? Gene Therapy vs Pharmacology Sharon Lewin and Keith Jerome Moderator: Mark Harrington Mario Stevenson Ph.D University of Miami Miller School of Medicine. “There is ongoing replication under HAART”

2. A spirited debate!

4. What accounts for the extreme persistence of the viral reservoir? HAART stops all viral replication. Reservoir persistence is due to the intrinsic stability of the latently infected, resting CD4 T-cell. Residual replication continues due to incompletely suppressive HAART. Reservoirs are maintained by replenishment.

5. Viral surrogates in suppressive HAART? Sequence evolution Immune activation/inflammation Latently infected cell frequency Cell-associated viral RNA Residual viremia cDNA intermediates

6. Cytoplasm Nucleus ~10%

7. Cytoplasm Nucleus  Raltegravir  

8. Episomes increase upon Raltegravir intensification. Buzon et al., Nature Med. 2010

9.  Raltegravir   Therefore, an increase in episomes following Raltegravir intensification can only be explained by de novo infection. An increase in episomes requires: -infectious virions. -de novo viral synthesis of viral cDNA

10. The low level of replication may be insufficient for resistance development. A chronic virus source drives limited rounds of infection. If there is continued infection under HAART, why don’t we see development of resistance?

11. de novo infection: ongoing versus chronic infection.

13. Let’s ponder the issues and hopefully, come up with a rational game plan.

15. Years on completely suppressive HAART Infectious virus Intrinsic stability versus replenishment Time to eradication 6040200 intrinsic stability replenishment 0

16. Monitoring the impact of treatment intensification: INTegRAL study by J. Picado, B. Clotet et al: impact of Raltegravir intensification. 69 patients on suppressive 3 drug HAART regimen randomized to intensify with Raltegravir (n=44) or to continue HAART (n=24). Episomal cDNA and immune activation parameters were monitored.