Higher percentages of regulatory T cells (Treg) were also found in the gut mucosa of HIV-infected subjects and SIV-infected rhesus macaques ( 3, 4). Notably, the loss of Th17 cells occurring during pathogenic SIV infection was accompanied with increased numbers of Th1 cells and reduction of IL-21-producing Th (Th21) cells ( 2, 7). Depletion of Th17 cells during SIV infection in rhesus macaques was also associated with enhanced dissemination of Salmonella enterica serovar Typhimurium from intestinal mucosa to mesenteric lymph nodes ( 6). Notably, Th17 depletion was apparent even at the early stages of pathogenic simian immunodeficiency (SIV) infection of rhesus macaques but not in the disease-free infection of the natural hosts African green monkeys or sooty mangabeys ( 3, 5). Depletion of this specific Th subset has been shown to associate with increased translocation of bacterial products across the mucosal barrier, increased viral loads, and immune hyperactivation associated with HIV disease ( 2– 4). Th17 cells secrete interleukin 17 (IL-17) and other cytokines that play a critical role in maintaining mucosal integrity and control of bacterial and fungal infections ( 1). The loss of Th17 cells in particular has been implicated in HIV disease progression in humans and animal models. In recent years, a number of studies have focused on examining the specific T helper (Th) cell subsets affected by HIV infection. The main target of human immunodeficiency virus (HIV) infection is CD4 T cells, and their loss leads ultimately to AIDS. These results indicate that features unique to Th17 cells, including higher expression of HIV receptors and lack of autocrine CCR5 ligands, are associated with enhanced permissiveness of these cells to HIV. Moreover, unlike Th1 cells, Th17 cells produced little CCR5 ligand, and transfection with one of the CCR5 ligands, MIP-1β (CCL4), increased their resistance against HIV. The cells also had greater expression of CD4 and CXCR4, but not CCR5, than CCR6 − cells. In identifying cellular factors contributing to higher susceptibility of Th17 cells to HIV, we compared Th17-enriched CCR6 + and Th17-depleted CCR6 − CD4 T cell cultures and noted that Th17-enriched CCR6 + cells expressed higher levels of α4β7 and bound HIV envelope in an α4β7-dependent manner. Th17 loss correlated with greater levels of virus-infected cells and cell death. HIV infection of these cultures had minimal effects on Th1 cells but caused depletion of Th17 cells. To investigate the differential effects of HIV infection on Th17 and Th1 cells, a culture system was used in which CCR6 + CD4 + T cells were sorted from healthy human peripheral blood and activated in the presence of interleukin 1β (IL-1β) and IL-23 to drive expansion of Th17 cells while maintaining Th1 cells. During chronic human immunodeficiency virus (HIV) infection, Th17 cells were more depleted compared to Th1 cells, even when the patients had low or undetectable viremia. Th17 cells are enriched in the gut mucosa and play a critical role in maintenance of the mucosal barrier and host defense against extracellular bacteria and fungal infections.
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