The role of Vpr in a primary CD4+ T-cell model of HIV-1 latency 3672

Abstract Description The primary obstacle to HIV-1 cure is the persistence of a long-lived latent reservoir, best characterized in memory CD4+ T cells. New research supports latency prevention as a therapeutic strategy. However, this approach will require a better understanding of how HIV-1 establishes latency. We recently showed using a primary CD4+ T-cell model that histone deacetylases (HDACs) are critical for latency entry. The role of viral factors, however, is unknown. We sought to determine how the cytotoxic HIV-1 protein Vpr, both alone and in combination with the HDAC inhibitor vorinostat (VOR), regulates HIV-1 latency establishment. In a primary CD4+ T-cell model, we observed a p300-dependent synergy between Vpr and VOR in maintaining viral gene expression. Using a selective p300 histone acetyltransferase (HAT) inhibitor, we observed that p300 HAT activity may be required. Interestingly, Vpr expression also resulted in an increased relative frequency of central memory T cells (TCM), the cell type in which the latent HIV-1 reservoir is enriched. Our preliminary results provide evidence that the increased proportion of TCM-like cells may be due to relatively lower levels of Vpr-induced apoptosis in these cells compared with other compartments. Vpr may therefore play an important role in shaping the latent reservoir. An improved understanding of how both viral and host factors affect latent reservoir formation will aid in the development of new latent HIV-1 reservoir-targeting therapies. Funding Sources Supported by NIH CARE Collaboratory 1UM1AI126619 and NIH 1R01AI143381-01A1 Topic Categories Viral Immunology (VIR)