Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

Despite considerable progress made in our understanding of HIV infection, we still do not completely understand how the virus causes AIDS and how it persists in infected individuals despite vigorous immune responses and highly suppressive antiretroviral regimens. Viral protein R (Vpr) is an HIV-encoded protein that is required for efficient infection of macrophages, a cell type that plays a major role in HIV persistence and pathogenesis. In addition, Vpr has the ability to arrest infected T lymphocytes at a specific step of the cell cycle (G2/M). Evidence from our laboratory indicate that these two biological activities are dependent on Vpr ability to engage the DDB1-CUL4(VPRBP) E3 ligase complex that is involved in conjugating ubiquitin to target proteins. Interestingly, recent studies have identified the SLX4 complex (SLX4com), which forms part of the Fanconi anemia DNA repair pathway, as a Vpr partner required for arresting cells at the G2/M. Association of Vpr/DDB1-CUL4(VPRBP) with the SLX4com triggered a premature activation of the SLX4com-containing endonuclease activity, a condition that led to G2/M arrest. Importantly, Vpr interaction with SLX4com during HIV infection appeared linked to escape from some sort of innate immune detection. While these findings suggest a potential link between DNA repair processes involving the SLX4com and suppression of HIV innate immune detection, the detailed mechanisms underlying these processes and the virological reason for SLX4 activation by HIV still remain unclear. The overall goal of this research project is to test the hypothesis that Vpr-mediated activation of the SLX4com protects the HIV DNA genome from an innate DNA sensing pathway, thus promoting efficient infection through escape from antiviral responses. Ultimately, the elucidation of the interaction between Vpr and the SLX4com will lead to a heightened comprehension of HIV infection and persistence and will reveal additional targets for antiviral strategies.