Memory CCR6⁺CD4⁺ T cells are preferential targets for productive HIV type 1 infection regardless of their expression of integrin β₇

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 α₄β₇, a newly identified HIV-gp120 binding receptor. In this study, we investigated whether memory T cells coexpressing CCR6 and integrin β₇ 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 β₇ ^-R6⁺ and β₇ ⁺R6⁺ compared with β ₇ ^-R6^- and β₇ ⁺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 α₄ and β₇ 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 β₇, is a discriminative marker for memory T cells imprinted with a transcriptional program favorable to HIV replication. Nevertheless, given the ability of integrin β₇ to regulate cell migration into the GALT and bind HIV-gp120, CCR6⁺ T cells coexpressing integrin β₇ 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.