A major focus of the study during the past year has been to continue to better understand HIV-1 induced cell death and latency formation at the molecular and cellular levels and to test therapeutic interventions in animal models. The lab continued its ongoing studies of different factors to better understand T cell longevity during HIV infection. The results of these studies are designed to help uncover and define the mechanisms involved in CD4 T cell depletion by specific viral gene products and in the context of viral infection, as well as the processes that drive latent infection. It was found that viral DNA integration into the host chromosome triggers DNA-PK activation, leading to death of the majority of CD4 T cells infected with HIV-1. This process was found to correlate with cell cycle progression, and the relevant cellular and viral factors are being investigated. We have also identified a subset of lymphocytes (termed follicular T helper cells) that is preferentially infected and depleted by HIV-1 in lymphoid tissues, and the mechanistic and functional aspects of this finding are currently under study. In addition, the cellular pathway JAK-STAT was found to promote the survival and expansion of latently infected memory CD4 cells, and pharmacological inhibition of this pathway by FDA-approved drugs led to the destruction of latently infected cells in vitro. The effects of these inhibitors on the viral reservoir ex vivo are currently being tested.
| Cooper, Arik; Garcia, Mayra; Petrovas, Constantinos et al. (2013) HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature 498:376-9 |
