Mechanisms underlying damage to the tight epithelial barrier of the GI tract and microbial translocation during HIV infection. (a) In the absence of HIV infection, retinoic acid produced by CD103+ DCs helps to drive T cells and innate lymphoid cells (ILC) to produce IL-17 and IL-22, which contributes to a healthy epithelial barrier. B cells produce IgA in the lamina propria, which regulate microbial products in the lumen and prohibit microbes (purple rods) from interacting with and translocating across the epithelial barrier. Macrophages (Mφ) are capable of phagocytosing any bacterial products that translocate without a proinflammatory milieu. (b) However, during HIV infection, IL-17 and IL-22 producing lymphocytes are lost, both by direct infection of CD4+ T cells by HIV, and potentially by skewing of homeostatic responses to proinflammatory responses such as IFN-α production by plasmactyoid dendritic cells (pDCs). Further, hyperactivated macrophages no longer phagocytose bacterial products but respond with inflammatory cytokines such as TNF-α and IFN-α. In addition, decreased IgA may lead to decreased control of microbial products. Inflammation and loss of homeostatic cytokines such as IL-17 and IL-22 lead to damage to the tight epithelial barrier of the GI tract, allowing microbial products to translocate and furthering inflammation.