HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

Gut-associated lymphoid tissues are enriched in CCR6(+) Th17-polarized CD4(+) T cells that contribute to HIV-1 persistence during antiretroviral therapy (ART). This raises the need for Th17-targeted immunotherapies. In an effort to identify mechanisms governing HIV-1 permissiveness/persistence in gut-homing Th17 cells, we analyzed the transcriptome of CCR6(+) versus CCR6-T cells exposed to the gut-homing inducer retinoic acid (RA) and performed functional validations in colon biopsies of HIV-infected individuals receiving ART (HIV+ART). Although both CCR6(+) and CCR6-T cells acquired gut-homing markers upon RA exposure, the modulation of unique sets of genes coincided with preferential HIV-1 replication in RA-treated CCR6(+) T cells. This molecular signature included the upregulation of HIV-dependency factors acting at entry/postentry levels, such as the CCR5 and PI3K/Akt/mTORC1 signaling pathways. Of note, mTOR expression/phosphorylation was distinctively induced by RA in CCR6(+) T cells. Consistently, mTOR inhibitors counteracted the effect of RA on HIV replication in vitro and viral reactivation in CD4(+) T cells from HIV+ ART individuals via postentry mechanisms independent of CCR5. Finally, CCR6(+) versus CCR6-T cells infiltrating the colons of HIV+ ART individuals expressed unique molecular signatures, including higher levels of CCR5, integrin beta 7, and mTOR phosphorylation. Together, our results identify mTOR as a druggable key regulator of HIV permissiveness in gut-homing CCR6(+) T cells.