Disruption of gut epithelial barrier integrity is a major factor associated with gut and systemic inflammation during HIV infection by allowing microbial translocation (MT) across the intestinal cell barrier. One theory to explain increased MT during HIV infection is the disruption of epithelial tight junctions, which, in turn, allows increased mucosal penetration by luminal bacteria and bacterial antigens into the lamina propria of the gut and then into the systemic circulation resulting in inflammation. MT remains after cART, even in HIV-infected individuals in which significant virus suppression occurs. The cytokine interferon-gamma (IFN) increases gastrointestinal (GI) tract epithelial barrier permeability. The source of IFN- is puzzling especially given that early in the disease, infected patients have severely depleted intestinal CD4+ T-cells, including Th1 cells. Moreover, intestinal CD4+ T-cell recovery is relatively slow, so their contributions to IFN may be minimal at best. Although HIV-specific CD8+ T-cells provide a source of IFN during HIV infection, their response to HIV antigen is dampened during cART. Another major source of IFN is innate lymphocytes: natural killer cells (NK) and innate lymphoid cells (ILCs). Our preliminary data indicate that that there are higher frequencies of gut-derived NK/ILCs (including those that express the NK activation receptor, NKp44) that produce IFN 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 to 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 and tumor necrosis factor alpha (TNFa) and 4) inducing the expression of ligands on HIV-infected T-cells, which in turn, trigger pro-inflammatory NK/ILC1s to secrete IFN/TNFa. To address these hypotheses, we propose the following: Specific Aim 1: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to the induction of colonic inflammatory ILC3s. Specific Aim 2: To determine the mechanism in which HIV and HAMB contribute to increased frequencies of pro-inflammatory gut NK1/ILC1s. Specific Aim 3: To evaluate the relationship between gut NK/ ILC cytokine profiles, expression of NK/ILC activating receptor ligands, epithelial barrier function, and inflammation during untreated and treated HIV infection.
NIH ExPorter
NIH ExPorter