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The functional polarization of CD4+ T cells determines their antimicrobial effector profile, but may also impact the susceptibility to infection with HIV-1. Here, we analyzed the susceptibility of CD4+ T cells with different functional polarization to infection with X4 and R5-tropic HIV-1.CD4+ T cells with a Th1, Th2, Th17, and Th9 polarization were subjected to in-vitro infection assays with X4, R5, or vesicular stomatitis virus-G protein-pseudotyped HIV-1. In addition, we sorted differentially polarized CD4+ T-cell subsets from individuals treated with antiretroviral therapy and analyzed the tropism of viral env sequences.Th9-polarized CD4+ T cells and, to a lesser extent, Th2-polarized CD4+ T cells expressed higher surface levels of CXCR4, and are more permissive to X4-tropic infection in vitro. In contrast, Th1 and Th17 CD4+ T cells exhibited stronger surface expression of CCR5, and were more susceptible to infection with R5-tropic viruses. Correspondingly, the distribution of X4-tropic viral sequences in antiretroviral therapy-treated HIV-1-infected patients was biased toward Th9/Th2 cells, whereas R5-tropic sequences were more frequently observed in Th17 cells.CD4+ T-cell polarization is associated with a distinct susceptibility to X4 and R5-tropic HIV-1 infection.