Preferential susceptibility of Th9 and Th2 CD4 T cells to X4-tropic HIV-1 infection

OBJECTIVE: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. METHODS:CD4 T cells with a Th1, Th2, Th17 and Th9 polarization were subjected to in vitro infection assays with X4, R5 or VSV-G-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. RESULTS: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 ART-treated HIV-1-infected patients was biased towards Th9/Th2 cells, while R5-tropic sequences were more frequently observed in Th17 cells. CONCLUSION:CD4 T cell polarization is associated with a distinct susceptibility to X4- and R5-tropic HIV-1 infection.