Planas Delphine, Fert Augustine, Zhang Yuwei, Goulet Jean-Philippe, Richard Jonathan, Finzi Andrés, Ruiz Maria Julia, Marchand Laurence Raymond, Chatterjee Debashree, Chen Huicheng, Wiche Salinas Tomas Raul, Gosselin Annie, Cohen Eric A, Routy Jean-Pierre, Chomont Nicolas, Ancuta Petronela
Département de microbiologie, infectiologie et immunologie; Faculté de médecine; Université de Montréal; Montréal, Québec, Canada.
Centre de recherche du CHUM; Montréal, Québec, Canada.
Pathog Immun. 2020 Sep 30;5(1):177-239. doi: 10.20411/pai.v5i1.348. eCollection 2020.
The frequency and functions of Th17-polarized CCR6RORytCD4 T cells are rapidly compromised upon HIV infection and are not restored with long-term viral suppressive antiretroviral therapy (ART). In line with this, Th17 cells represent selective HIV-1 infection targets mainly at mucosal sites, with long-lived Th17 subsets carrying replication-competent HIV-DNA during ART. Therefore, novel Th17-specific therapeutic interventions are needed as a supplement of ART to reach the goal of HIV remission/cure. Th17 cells express high levels of (PPARy), which acts as a transcriptional repressor of the HIV provirus and the gene, which encodes for the Th17-specific master regulator RORyt. Thus, we hypothesized that the pharmacological inhibition of PPARy will facilitate HIV reservoir reactivation while enhancing Th17 effector functions. Consistent with this prediction, the PPARy antagonist T0070907 significantly increased HIV transcription (cell-associated HIV-RNA) and RORyt-mediated Th17 effector functions (IL-17A). Unexpectedly, the PPARy antagonism limited HIV outgrowth from cells of ART-treated people living with HIV (PLWH), as well as HIV replication . Mechanistically, PPARy inhibition in CCR6CD4 T cells induced the upregulation of transcripts linked to Th17-polarisation (RORyt, STAT3, BCL6 IL-17A/F, IL-21) and HIV transcription (NCOA1-3, CDK9, HTATIP2). Interestingly, several transcripts involved in HIV-restriction were upregulated (Caveolin-1, TRIM22, TRIM5α, BST2, miR-29), whereas HIV permissiveness transcripts were downregulated (CCR5, furin), consistent with the decrease in HIV outgrowth/replication. Finally, PPARy inhibition increased intracellular HIV-p24 expression and prevented BST-2 downregulation on infected T cells, suggesting that progeny virion release is restricted by BST-2-dependent mechanisms. These results provide a strong rationale for considering PPARy antagonism as a novel strategy for HIV-reservoir purging and restoring Th17-mediated mucosal immunity in ART-treated PLWH.
在感染HIV后，向Th17极化的CCR6RORytCD4 T细胞的频率和功能迅速受损，并且长期的病毒抑制性抗逆转录病毒疗法（ART）无法使其恢复。与此一致的是，Th17细胞主要在黏膜部位成为HIV-1的选择性感染靶点，在接受ART治疗期间，长寿的Th17亚群携带具有复制能力的HIV-DNA。因此，需要新的针对Th17的治疗干预措施作为ART的补充，以实现HIV缓解/治愈的目标。Th17细胞高水平表达（PPARy），其作为HIV前病毒和编码Th17特异性主调节因子RORyt的基因的转录抑制因子。因此，我们假设PPARy的药理学抑制将促进HIV储存库的重新激活，同时增强Th17效应功能。与这一预测一致，PPARy拮抗剂T0070907显著增加了HIV转录（细胞相关HIV-RNA）和RORyt介导的Th17效应功能（IL-17A）。出乎意料的是，PPARy拮抗作用限制了HIV从接受ART治疗的HIV感染者（PLWH）的细胞中生长，以及HIV复制。从机制上讲，CCR6CD4 T细胞中PPARy的抑制诱导了与Th17极化相关转录本（RORyt、STAT3、BCL6 IL-17A/F、IL-21）和HIV转录（NCOA1-3、CDK9、HTATIP2）的上调。有趣的是，一些参与HIV限制的转录本上调（小窝蛋白-1、TRIM22、TRIM5α、BST2、miR-29），而HIV允许性转录本下调（CCR5、弗林蛋白酶），这与HIV生长/复制的减少一致。最后，PPARy抑制增加了细胞内HIV-p24表达，并防止感染T细胞上BST-2下调，表明子代病毒体释放受到BST-2依赖性机制的限制。这些结果为将PPARy拮抗作用作为清除HIV储存库和恢复接受ART治疗的PLWH中Th17介导的黏膜免疫的新策略提供了有力的理论依据。
