Eliminating the latent HIV reservoir by reactivation strategies: advancing to clinical trials

Abstract

Combination antiretroviral therapy (cART) has transformed HIV from a deadly to a chronic disease, but HIV patients are still burdened with excess morbidity and mortality, long-term toxicities from cART, stigmatization, and insufficient access to cART worldwide. Thus, a cure for HIV would have enormous impact on society as well as the individual. As the complexity and mechanisms of HIV persistence during therapy are being unraveled, new therapeutic targets for HIV eradication are discovered. Substances that activate HIV production in the latently infected cells have recently received much attention. By turning on expression of latent HIV proviruses, reactivation strategies could contribute to the eradication HIV infection. Compounds that are currently being or soon to be tested in clinical trials are emphasized. The results from these trials will provide important clues as to whether or not reactivating strategies could become significant components of a cure for HIV.

Keywords: HIV; cure; experimental research; histone deacetylase inhibitors; immune modulation.

Figure 1. Disruption of HIV latency by HDAC Inhibitors. In the latent state HDACs suppresses HIV-1 expression by catalyzing deacetylation of histone tails and keeping the chromatin in a compacted state. Inhibition of HDACs by HDACi promotes histone acetylation by HATs leading to relaxation of the chromatin and initiation of transcription. HDACs: histone deacetylases; HDACi: histone deacetylase inhibitors; HATs: histone acetyl transferases; LTR: long-terminal repeat.

Figure 2. Stimulation of HIV-1 expression by CpG 2006 and panobinostat. HIV-1 expression in the latently infected cell line U1 following treatment for 48 h with combinations of CpG 2006 (0–10 μg/mL) and panobinostat (LBH589; 0–15nM). Virus production was estimated by p24 levels in supernatant; mean +/− SEM shown in figure