Cooperativity of HIV-specific cytolytic CD4 T cells and CD8 T cells in control of HIV viremia

CD4⁺ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4⁺ T cell functions beyond helper effects have been described, and a role for cytolytic CD4⁺ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4⁺ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4⁺ T cells revealed a distinct transcriptional signature compared to Th1 CD4⁺ cells but shared similar features with HIV-specific cytolytic CD8⁺ T cells. Furthermore, HIV-specific cytolytic CD4⁺ T cells showed comparable killing activity relative to HIV-specific CD8⁺ T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4⁺ T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4⁺ T cells as an independent subset distinct from Th1 cells that show combined activity with CD8⁺ T cells in the long-term control of HIV infection.