Basic Science Award

The depletion of CD4 T cells and development of chronic inflammation represent signature pathological processes centrally contributing to clinical progression of HIV disease. Current therapy chiefly diminishes viral replication. Novel therapeutics preventing CD4 T-cell depletion and/or reducing chronic inflammation could form valuable adjuncts to antiviral medications potentially improving long-term clinical outcomes including limiting the early appearance of diseases associated with aging. Our studies suggest that these signature processes are, in fact, interrelated. Most CD4 T cells dying during untreated HIV infection are not mere cellular bystanders but, instead, are abortively infected with HIV1. Surprisingly, these abortively infected cells die as result of an innate immune response launched against the incomplete viral reverse transcripts that accumulate in the cytosol. These DNAs triggers inflammasome assembly, caspase-1 activation, processing of pro-IL-1?, and the induction of a highly inflammatory pathway of programmed cell death termed pyroptosis. The execution of this death pathway provides an intriguing link between CD4 T-cell depletion and chronic inflammation. Strikingly, I find that activation of the pyroptotic pathway requires cell-to-cell transmission of HIV virions. Why cell-free virons are ineffective and what properties of the virological synapse are required to elicit pyroptosis represent key unanswered questions that I propose to address in Specific Aim 1. Additionally, my proposed studies will also explore key differences that distinguish pathogenic versus nonpathogenic lentiviral infections. Specifically I hypothesize that the pyroptosis pathway is not engaged with less pathogenic lentiviruses like HIV-2. The Vpx protein encoded by HIV-2 may contribute through its ability to degrade the SAMHD1 host restriction factor present in quiescent nonpermissive cells. Vpx action may render these cells permissive to infection thwarting the abortive infection that depends on SAMHD1 action (Specific Aim 2). This action of Vpx could result in a milder clinical disease course as observed in HIV-2 infected individuals compared to HIV-1-infected subjects. Together, these studies promise to provide a deeper understanding of the mechanisms underlying the two signature processes characteristic of pathogenic HIV infection?CD4 T-cell death and chronic inflammation?and potentially to identify new therapeutic strategies for their prevention. This work will be completed within one-year period of time. If I am approved for CFAR support, my goal will be to leverage the results of my studies to secure longer term NIH funding that would propel the progress of my scientific career.