High-throughput screening uncovers a compound that activates latent HIV-1 and acts cooperatively with a histone deacetylase (HDAC) inhibitor.

Current antiretroviral therapy (ART) provides potent suppression of HIV-1 replication. However, ART does not target latent viral reservoirs, so persistent infection remains a challenge. Small molecules with pharmacological properties that allow them to reach and activate viral reservoirs could potentially be utilized to eliminate the latent arm of the infection when used in combination with ART. Here we describe a cell-based system modeling HIV-1 latency that was utilized in a high-throughput screen to identify small molecule antagonists of HIV-1 latency. A more detailed analysis is provided for one of the hit compounds, antiviral 6 (AV6), which required nuclear factor of activated T cells for early mRNA expression while exhibiting RNA-stabilizing activity. It was found that AV6 reproducibly activated latent provirus from different lymphocyte-based clonal cell lines as well as from latently infected primary resting CD4(+) T cells without causing general T cell proliferation or activation. Moreover, AV6 complemented the latency antagonist activity of a previously described histone deacetylase (HDAC) inhibitor. This is a proof of concept showing that a high-throughput screen employing a cell-based model of HIV-1 latency can be utilized to identify new classes of compounds that can be used in concert with other persistent antagonists with the aim of viral clearance.

Short communication: activation of latent HIV type 1 gene expression by suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor approved for use to treat cutaneous T cell lymphoma.

The ability of HIV to establish a latent infection causes life-long virus persistence, even after long-term highly active antiretroviral therapy (HAART). The role that latency is playing in preventing clearance of the virus infection has become evident in recent years. Patients who have been successfully treated with ART, having undetectable levels of viral RNA (below 50 copies/ml) in the plasma for years, experienced rapid virus rebound on withdrawal of therapy. Activation of latent proviruses from the infected cells in combination with ART is a therapeutic strategy that may lead to the complete elimination of HIV infection. We report here that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor that has been approved for the treatment of cutaneous T cell lymphoma (CTCL), can activate an HIV-1 vector provirus in a cell model system. Treatment of cells harboring a latent, HIV-1-derived provirus caused activation of both early and late viral gene expression, acetylation of nucleosome on the 5' long terminal repeat (LTR), and remodeling of the chromatin at the 5' LTR. Several compounds, including valproic acid, have been tested for their ability to activate latent HIV-1, but have met with disappointing results. SAHA, a relatively nontoxic, FDA-approved compound, should be considered for developing a strategy to eliminate HIV from patients.