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标题：Th17 cell master transcription factor RORC2 regulates HIV-1 gene expression and viral outgrowth
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作者：Tomas Raul Wiche Salinas ; Yuwei Zhang ; Daniele Sarnello 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：48
DOI：10.1073/pnas.2105927118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance HIV-1 infects CD4 T cells, and, among these, T helper 17 (Th17) cells are known to be particularly permissive for virus replication. The infection of Th17 cells is critical for AIDS pathogenesis and viral persistence. It is, however, not clear why these cells are highly permissive to HIV-1. We found that Th17 cell permissiveness depends on the expression of the hormone receptor RORC2, which is the master transcriptional regulator of Th17 cell differentiation. We identify RORC2 as a cell-specific host-dependency factor that can be targeted by small molecules. Our results suggest that RORC2 may be a cell-specific target to mitigate the loss of Th17 cells as a consequence of their preferential HIV-1 infection. Among CD4 + T cells, T helper 17 (Th17) cells are particularly susceptible to HIV-1 infection and are depleted from mucosal sites, which causes damage to the gut barrier, resulting in a microbial translocation-induced systemic inflammation, a hallmark of disease progression. Furthermore, a proportion of latently infected Th17 cells persist long term in the gastrointestinal lymphatic tract where a low-level HIV-1 transcription is observed. This residual viremia contributes to chronic immune activation. Thus, Th17 cells are key players in HIV pathogenesis and viral persistence. It is, however, unclear why these cells are highly susceptible to HIV-1 infection. Th17 cell differentiation depends on the expression of the master transcriptional regulator RORC2, a retinoic acid-related nuclear hormone receptor that regulates specific transcriptional programs by binding to promoter/enhancer DNA. Here, we report that RORC2 is a key host cofactor for HIV replication in Th17 cells. We found that specific inhibitors that bind to the RORC2 ligand-binding domain reduced HIV replication in CD4 + T cells. The depletion of RORC2 inhibited HIV-1 infection, whereas its overexpression enhanced it. RORC2 was also found to promote HIV-1 gene expression by binding to the nuclear receptor responsive element in the HIV-1 long terminal repeats (LTR). In treated HIV-1 patients, RORC2 + CD4 T cells contained more proviral DNA than RORC2 − cells. Pharmacological inhibition of RORC2 potently reduced HIV-1 outgrowth in CD4 + T cells from antiretroviral-treated patients. Altogether, these results provide an explanation as to why Th17 cells are highly susceptible to HIV-1 infection and suggest that RORC2 may be a cell-specific target for HIV-1 therapy.
关键词：HIV-1; RORC2; Th17; gene expression; hormone receptor