Does non-pyroptotic IFI16 signaling promote HIV pathogenesis by recruiting new target cells to die?
Award amount: 40,000.00
Untreated HIV infection is distinguished by two major clinical hallmarks: progressive depletion of CD4 T cells, and chronic inflammation. We now know that resting “bystander” CD4 T cells in lymphoid tissue undergo a process of abortive HIV infection where incomplete reverse transcripts are formed and detected by the host DNA sensor, interferon gamma-inducible protein 16 (IFI16). This activation of IFI16 causes the assembly of an inflammasome, which cleaves caspase-1 and causes pyroptosis in the CD4 T cell. Pyroptosis is a highly inflammatory form of programmed cell death, which drives a pathogenic cycle where abortive infection, pyroptotic cell death, and inflammation somehow attract new cells to die. It remains unclear what signals mediate the attraction of new cells to “fuel the fire.” We hypothesize that a second non-pyroptotic signaling activity of IFI16 plays a key role in target cell recruitment. Our objective is to explore whether IFI16 signaling through STING and STAT-6 leads to the production of the CCL2 chemokine, mediating target cell recruitment. We plan to test if CCL2 produced by ex vivo human lymphoid aggregate cultures infected with HIV is IFI16-dependent. In preliminary studies, we identified a new subset of central memory CD4 T cells that express CCR2, the receptor for CCL2. We propose to test the function of CCL2 to recruit CCR2+ CD4 T cells through transwell cultures. In parallel, we will use immunohistochemistry to examine lymph node samples from untreated HIV-infected individuals for increased CCL2, and abundance of CCR2-expressing memory CD4 T cell in zones of pyroptosis (caspase-1 positive) in the paracortical region, as compared to uninfected or ART-treated individuals. We anticipate that our studies and statistical analyses can be completed in one year. We believe that this work will advance our understanding of how CD4 T cells are recruited and depleted during HIV infection.