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

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms.
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Planas D, Zhang Y, Monteiro P, Goulet JP, Gosselin A, Grandvaux N, Hope TJ, Fassati A, Routy JP, Ancuta P,


Planas D, Zhang Y, Monteiro P, Goulet JP, Gosselin A, Grandvaux N, Hope TJ, Fassati A, Routy JP, Ancuta P, (click to view)

Planas D, Zhang Y, Monteiro P, Goulet JP, Gosselin A, Grandvaux N, Hope TJ, Fassati A, Routy JP, Ancuta P,

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JCI insight 2017 08 032(15) doi 10.1172/jci.insight.93230

Abstract

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 β7, and mTOR phosphorylation. Together, our results identify mTOR as a druggable key regulator of HIV permissiveness in gut-homing CCR6+ T cells.

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