 Switch from homeostatic to inflammatory cytokines by NK/ILC in HIV-infected gut
 Biography Overview ? DESCRIPTION (provided by applicant): Loss of TH22 during HIV infection may contribute to decreased IL-22 presence in the gut; however, a subpopulation of innate lymphoid cells (ILCs), mainly NKp44 activation receptor expressing ILC3, is capable of maintaining IL-22 levels even when T-cells are depleted in the gastrointestinal (GI) tract. Our preliminary data indicate that that there are higher frequencies of gut-derived Natural Killer cells (NK)/ILCs (including those that express NKp44) that produce interferon-gamma (IFN-j) when they were obtained from viremic HIV-infected individuals as compared to cells obtained from the GI tract of uninfected individuals. We hypothesize that HIV creates an environment that alters the function of NK/ILCs from cells that are important in maintaining homeostasis in the GI tract to cells that contribute t increased inflammation and barrier dysfunction in the gut of infected patients. We postulate that HIV both directly and indirectly induces inflammatory NK/ILC by 1) stimulating intestinal myeloid dendritic cells (mDC) to secrete pro-inflammatory cytokines 2) modifying the gut microbiome to increase pathobiont bacteria, which in turn trigger mDCs to secrete higher levels of pro- inflammatory cytokines 3) inducing the expression of ligands to NKp44 on CD4+ T-cells which trigger ILC3s (which normally secrete IL-22) to begin secreting IFN-j and TNF-a and 4) inducing the expression of ligands on HIV-infected T-cells, which in turn, trigger pro-inflammatory NK/ILC1s to secrete IFN-j/TNF-a. To address these hypotheses, we propose the following: Specific Aim 1: To evaluate the relationship between gut NK/ ILC cytokine profiles, expression of NK/ILC activating receptor ligands, and epithelial barrier function in untreated HIV infection and to determine whether associations exist between gut NK/ILC cell inflammatory cytokine production and clinical correlates of HIV pathogenesis in HIV-infected subjects on suppressive cART. Specific Aim 2: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to the induction of colonic inflammatory ILC3s Aim 3: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to increased frequencies of pro-inflammatory NK1/ILC1s.
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