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HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms
Delphine Planas, … , Jean-Pierre Routy, Petronela Ancuta
Delphine Planas, … , Jean-Pierre Routy, Petronela Ancuta
Published August 3, 2017
Citation Information: JCI Insight. 2017;2(15):e93230. https://doi.org/10.1172/jci.insight.93230.
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Research Article AIDS/HIV Immunology

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

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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.

Authors

Delphine Planas, Yuwei Zhang, Patricia Monteiro, Jean-Philippe Goulet, Annie Gosselin, Nathalie Grandvaux, Thomas J. Hope, Ariberto Fassati, Jean-Pierre Routy, Petronela Ancuta

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Figure 8

mTOR inhibitors limit HIV replication at postentry levels in ATRA-treated CD4+ T cells.

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mTOR inhibitors limit HIV replication at postentry levels in ATRA-treate...
(A–D) Memory CD4+ T cells were first analyzed for the surface expression of CCR5 and integrin β7 at day 4 after TCR triggering in the presence/absence of ATRA (10 nM), rapamycin (10 nM), and/or INK128 (50 nM). (A) Levels of CCR5 and (C) integrin β7 expression in one representative donor, and (B) statistical analysis of CCR5 (n = 3) and (D) integrin β7 (n = 5) expression in different donors (mean ± SEM). (E–G) Then, stimulated cells were exposed to VSV-G–pseudotyped HIV (25 ng HIV-p24/106 cells) (single round infection) and cultured in presence/absence of ATRA and/or rapamycin or INK128 for 3 additional days. (E) Levels of RU5, (F) Gag, and (G) integrated HIV DNA were quantified by nested real-time PCR in cells harvested at day 3 after infection. Relative HIV DNA levels (mean ± SEM; n = 3); the range of absolute HIV DNA copies/106 cells in ATRA-treated CCR6+ T cells (considered 100%) is indicated on the figure. Each symbol represents one different donor. Repeated-measures 1-way ANOVA with Tukey’s (B–D) or Dunnett’s (relative to cells stimulated via the TCR the presence of ATRA) (E–G) multiple comparisons tests (***P < 0.001; ****P < 0.0001).

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