Abstract
HIV type 1 infection is associated with a rapid depletion of Th17 cells from the GALT. The chemokine receptor CCR6 is a marker for Th17 lineage polarization and HIV permissiveness in memory CD4(+) T cells. CCR6(+) T cells have the potential to migrate into the GALT via the gut-homing integrin α(4)β(7), a newly identified HIV-gp120 binding receptor. In this study, we investigated whether memory T cells coexpressing CCR6 and integrin β(7) are selective HIV targets and whether retinoic acid (RA)-induced imprinting for gut-homing selectively increases CCR6(+) T cell permissiveness to infection. We demonstrated that β(7)(-)R6(+) and β(7)(+)R6(+) compared with β(7)(-)R6(-) and β(7)(+)R6(-) T cells were highly permissive to HIV, produced Th17 cytokines, and their frequency was decreased in the peripheral blood of HIV-infected subjects. RA upregulated integrin α(4) and β(7) coexpression in both CCR6(+) and CCR6(-) T cells, but increased HIV permissiveness selectively in CCR6(+) T cells via entry (CCR5 upregulation) and postentry mechanisms. In conclusion, these results demonstrate that CCR6, but not the integrin β(7), is a discriminative marker for memory T cells imprinted with a transcriptional program favorable to HIV replication. Nevertheless, given the ability of integrin β(7) to regulate cell migration into the GALT and bind HIV-gp120, CCR6(+) T cells coexpressing integrin β(7) and CCR5 might have an extraordinary ability to disseminate HIV from the portal sites of entry. Understanding the molecular mechanisms of memory CCR6(+) T cell differentiation is critical for the design of new therapeutic strategies that should interfere with viral permissiveness but not Th17 lineage commitment and gut-homing potential in CCR6(+) T cells.