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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DOI：
10.1172/jci.insight.93230
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发表时间：
2017-08-03
期刊：
影响因子：
8
通讯作者：
Ancuta, Petronela
中科院分区：
文献类型：
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作者：
Planas, Delphine;Zhang, Yuwei;Ancuta, Petronela
肠道相关淋巴组织富含 CCR6(+) Th17 极化 CD4(+) T 细胞，这些细胞有助于抗逆转录病毒治疗 (ART) 期间 HIV-1 的持续存在。这增加了对 Th17 靶向免疫疗法的需求。为了确定控制肠道归巢 Th17 细胞中 HIV-1 允许性/持久性的机制，我们分析了暴露于肠道归巢诱导剂视黄酸 (RA) 的 CCR6(+) 与 CCR6-T 细胞的转录组，并在接受 ART (HIV+ART) 的 HIV 感染者的结肠活检中进行了功能验证。尽管 CCR6(+) 和 CCR6-T 细胞在 RA 暴露后都获得了肠道归巢标记，但独特基因组的调节与 RA 处理的 CCR6(+) T 细胞中的优先 HIV-1 复制相一致。该分子特征包括在进入/进入后水平发挥作用的 HIV 依赖性因子的上调，例如 CCR5 和 PI3K/Akt/mTORC1 信号通路。值得注意的是，在 CCR6(+) T 细胞中，mTOR 表达/磷酸化是由 RA 独特诱导的。一致地，mTOR抑制剂通过独立于CCR5的后进入机制抵消了RA对体外HIV复制和来自HIV+ART个体的CD4(+)T细胞中病毒再激活的影响。最后，浸润 HIV+ ART 个体结肠的 CCR6(+) 与 CCR6-T 细胞表达了独特的分子特征，包括更高水平的 CCR5、整合素 β 7 和 mTOR 磷酸化。总之，我们的结果确定 mTOR 是肠道归巢 CCR6(+) T 细胞中 HIV 许可性的可药物化关键调节剂。
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.