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

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 6

mTOR inhibitors counteract the effect of ATRA on HIV permissiveness in memory CD4+ T cells.

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mTOR inhibitors counteract the effect of ATRA on HIV permissiveness in m...
(A) The ability of mTOR inhibitors to counteract the effects of ATRA on HIV replication was tested in total memory CD4+ T cells. Briefly, total memory CD4+ T cells were stimulated via CD3/CD28 in presence/absence of ATRA and/or rapamycin (10 nM) or INK128 (50 nM) for 4 days. Then, cells were exposed to replication-competent T/F HIV THRO (25 ng HIV-p24/106 cells). Further, cells were cultured for 9 additional days in presence/absence of ATRA and/or rapamycin or INK128. (B–D) The relative RU5, Gag, and integrated HIV DNA levels quantified by real-time nested PCR at day 3 after infection (with the range of absolute HIV DNA copies/106 cells in ATRA-treated cells, considered 100%, being indicated in the figure) and (E) HIV-p24 levels quantified by ELISA in cell culture supernatants at days, 3, 6 and 9 after infection (n = 5, mean ± SEM) shown. Each symbol represents one different donor. Repeated-measures 1-way ANOVA (B–E), with Dunnett’s (relative to cells stimulated via the TCR in the presence of ATRA) (B–D) or Tukey’s (E) multiple comparisons test (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001).