There remains another DAPT possibility (perhaps a less popular view) that there is continued low rate of HIV replication. Two clinical studies have been initiated in subjects with undetectable plasma HIV levels. Raltegravir, an HIV integrase inhibitor, was added to the background therapy. Latent HIV is mostly integrated into host DNA but HIV may also form episomal circular DNA. The proportion of the circular form increases with raltegravir treatment. In the two clinical studies,

13/45 and 9/15 subjects, respectively, had detectable HIV circles which then decayed. This implies that some de novo infection of cells is ongoing. On the other hand, ART works well, with no evidence of sequence evolution in the HIV circles at 48 weeks. Is it possible that raltegravir is inducing a single round of HIV replication, to give an increase in HIV circles? Derek Sloan, Gilead Sciences, Foster City, CA, USA Like vorinostat, (VOR), romidepsin (RMD) is a histone

deacetylase inhibitor which is used clinically to treat cancer. Memory CD4+ T cells were taken from HIV subjects on suppressive ART; ex-vivo treatment with RMD (40 nM) induced a 6-fold increase in intracellular HIV RNA which persisted for 48 h. In contrast, a much higher concentration of VOR INCB018424 (1 μM) gave a 2 to 3-fold lower response which was only transient. RMD also increased levels of extracellular HIV RNA and virions. Encouragingly, IKBKE this ex-vivo induction of latent virus was seen at RMD concentrations that are below the levels of drug achieved in humans by clinical doses of RMD. Accordingly, in a Phase I/II trial in HIV-infected subjects on ART, RMD gave a better and more sustained response than VOR. About 1.5% of cells containing HIV provirus were activated. Although this is far too low a percentage to eliminate the latent

HIV reservoir, it is hoped that combination of such LRA, which give improved results in ex-vivo cell assays, may give better clinical efficacy. Gilead scientists have started screening for novel LRAs. “GS-1” has been identified as a hit by HTS. Research on this lead is at a very early stage. Gilead workers are also investigating other approaches. For example, GS-9620 is a Toll-like receptor 7 (TLR7) agonist and it acts as an immune stimulator. Although it is being evaluated in Phase II studies for the treatment of chronic HBV infections, the potential effect on HIV reservoirs is being investigated. In SIV-infected monkeys, oral dosing of TLR7 agonist induced the activation of immune effector cells such as CD8+ T cells and NK cells. Based on these data, TLR7 agonists are being further investigated for their effect on latent SIV reservoirs in monkeys which have good virological suppression. Another approach is to use anti-envelope antibodies.