Human immunodeficiency virus (HIV) infects and depletes CD4⁺ T cells, but subsets of CD4⁺ T cells vary in their susceptibility and permissiveness to infection. For example, HIV preferentially depletes interleukin-17 (IL-17)-producing T helper 17 (T_h17) cells and T follicular helper (T_fh) cells. The preferential loss of T_h17 cells during the acute phase of infection impairs the integrity of the gut mucosal barrier, which drives chronic immune activation—a key determinant of disease progression. The preferential loss of T_h17 cells has been attributed to high CD4, CCR5, and CXCR4 expression. Here, we show that T_h17 cells also exhibit heightened permissiveness to productive HIV infection. Primary human CD4⁺ T cells were sorted, activated under T_h17- or T_h0-polarizing conditions and infected, and then analyzed by flow cytometry. T_h17-polarizing cytokines increased HIV infection, and HIV infection was disproportionately higher among T_h17 cells than among IL-17⁻ or gamma interferon-positive (IFN-γ⁺) cells, even upon infection with a replication-defective HIV vector with a pseudotype envelope. Further, T_h17-polarized cells produced more viral capsid protein. Our data also reveal that T_h17-polarized cells have diminished expression of RNase A superfamily proteins, and we report for the first time that RNase 6 inhibits HIV. Thus, our findings link T_h17 polarization to increased HIV replication.

IMPORTANCE Our study compares the intracellular replicative capacities of several different HIV isolates among different T cell subsets, providing a link between the differentiation of T_h17 cells and HIV replication. T_h17 cells are of key importance in mucosal integrity and in the immune response to certain pathogens. Based on our findings and the work of others, we propose a model in which HIV replication is favored by the intracellular environment of two CD4⁺ T cell subsets that share several requirements for their differentiation: T_h17 and T_fh cells. Characterizing cells that support high levels of viral replication (rather than becoming latently infected or undergoing cell death) informs the search for new therapeutics aimed at manipulating intracellular signaling pathways and/or transcriptional factors that affect HIV replication.