Although antiretroviral therapy (ART) has dramatically improved the clinical prognosis for people with HIV and prevents transmission, ART is not a cure. This is because of a latent reservoir that persists in long-lived cells such as central memory CD4+ T (TCM) cells. Eliminating this reservoir will require a better understanding of HIV-1 latency establishment. We and others have recently shown that histone deacetylases (HDACs) are critical cellular factors that allow HIV-1 entry into latency. We also demonstrated that the HDAC inhibitor (HDACi) vorinostat reprograms cells from a stem-cell memory-like phenotype to a TCM phenotype. It is unknown, however, whether HDACs interact with specific viral factors to regulate latency establishment. To examine the role of individual HIV-1 accessory proteins, we constructed a panel of HIV-1 reporter strains and examined them in a primary CD4+ T-cell latency model. Interestingly, we found that vorinostat potently enhances the effect of the HIV-1 protein Vpr in promoting HIV expression in infected cells, suggesting that Vpr possesses a cryptic pro-transcription 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 TCM phenotype. These TCM-like 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. Finally, given the combined pro-transcriptional effect or Vpr and vorinostat, we assessed whether virus-like particle-mediated delivery of Vpr could enhance the latency reversal potential of vorinostat. Although we did not see a strong combined effect, Vpr alone significantly reversed latency to a greater extent than vorinostat alone, suggesting that Vpr has potential as a latency reversal agent. Future work will benefit from exploring different Vpr delivery modes and combining Vpr with other latency reversal agents. Overall, understanding how viral factors shape the latent reservoir and how host and viral factors interact during HIV-1 latency establishment and maintenance in CD4+ T cells will aid in the development of new latency-targeting therapies.