HIV-1 accessory protein Vpr possesses a cryptic p300-dependent transcription-promoting activity that is blocked by histone deacetylases in CD4+ T cells.

Antiretroviral therapy (ART) has dramatically improved the clinical prognosis for people with HIV and prevents HIV transmission. However, ART does not cure HIV infection because of a persistent, latent reservoir in long-lived cells such as central memory CD4+ T (TCM) cells. Eliminating or preventing reservoir formation will require a better understanding of HIV-1 latency establishment. We and others have recently shown that host cell factors such as histone deacetylases (HDACs) are critical cellular factors that allow HIV-1 entry into latency. Whether HDACs interact with specific viral factors to regulate latency establishment, however, is unknown. To examine the role of individual HIV-1 accessory proteins, we constructed a panel of HIV-1 reporter strains, each expressing a single HIV-1 accessory protein, and examined them in a primary CD4+ T-cell latency model. Interestingly, we found that the HDAC inhibitor (HDACi) vorinostat potently enhances the effect of the HIV-1 protein Vpr in promoting HIV expression in infected cells, suggesting that Vpr possesses a cryptic transcription-promoting activity that is restricted by HDACs. This activity was dependent on a p300-binding domain of Vpr and inhibited by a selective p300 histone acetyltransferase inhibitor. Interestingly, Vpr expression also resulted in a significant increase in the proportion of infected cells with a central memory (TCM) phenotype. Furthermore, we observed that TCM cells were more resistant to Vpr-induced apoptosis/cell death than other CD4+ T-cell subtypes, indicating that Vpr expression during reservoir formation selects for latent proviruses in TCM cells. Overall, these findings suggest that Vpr plays an important role in shaping the latent reservoir and that HIV-1 latency results, in part, from an HDAC-mediated restriction on Vprs transcription-promoting activity. Understanding how viral factors shape the latent reservoir and how host and viral factors interact during HIV-1 latency establishment in CD4+ T cells will aid in the development of new latency-targeting therapies. Author SummaryAlthough antiretroviral therapy is effective at treating HIV, a cure remains elusive. The primary obstacle to HIV cure is the presence of a long-lived reservoir of latently infected cells in which the virus persists despite therapy. Recent work has shown that a sizable fraction of this latent reservoir forms near the time that therapy is initiated, suggesting it may be possible to prevent some of the reservoir from forming. However, latency prevention will require a better understanding of how HIV enters latency, including how viral gene expression is silenced. We therefore sought to examine the role of the interaction between viral proteins and host factors in turning off viral gene expression and found that, whereas the HIV protein Vpr turns on viral gene expression, host histone deacetylases block this activity. Second, we observed that Vpr expression in infected cells leads to an increase in the relative proportion of central memory CD4+ T cells, a cell type that harbors latent virus. Our findings on the role of the viral protein Vpr in the silencing of viral gene expression and the persistence of certain memory cell types during infection will be important for developing new approaches to targeting latently infected cells.