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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 4

Components of the AKT/PI3K pathways modulated by ATRA in CCR6+ T cells.

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Components of the AKT/PI3K pathways modulated by ATRA in CCR6+ T cells.
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Memory CCR6+/CCR6– T cells were sorted and stimulated as described in Figure 1. Total RNA from matched T cell subsets of n = 6 different HIV-uninfected donors was used for genome-wide transcriptional profiling, as described in Figure 2. One-way ANOVA analysis identified differentially expressed genes based on P values or adjusted P values (P < 0.05) and/or fold-change (FC, cutoff 1.3). (A) Combined BIOCARTA_AKT_PATHWAY and PID_PI3K_PLC_TRK_PATHWAY canonical pathways significantly modulated by ATRA in CCR6+ T cells, identified using Ingenuity Pathway Analysis. (B) Gene expression network generated using individual genes representing REACTOME_MTORC1_MEDIATED_SIGNALING significantly modulated by ATRA in CCR6+ T cells identified through GSVA. The color code is based on expression FC (red and green for upregulated and downregulated transcripts, respectively). Nodes representing individual genes are annotated with their corresponding P values and FC (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001).
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