HIV-1-induced type I IFNs promote viral latency in macrophages.
HIV-1-induced type I IFNs promote viral latency in macrophages.
复制标题
HIV-1诱导的I型IFN促进了巨噬细胞中的病毒潜伏期。
DOI：
10.1002/jlb.4ma0422-616r
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发表时间：
2022-11
影响因子：
5.5
通讯作者：
Hanley, Timothy M.
中科院分区：
文献类型：
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作者：
Dickey, Laura L.;Martins, Laura J.;Planelles, Vicente;Hanley, Timothy M.
长期感染HIV-1的巨噬细胞是抗逆转录病毒治疗期间HIV-1持续存在的储存库;然而，管理这种病毒储存库建立和维持的机制尚未完全阐明。在这里，我们发现HIV-1进入了一种让人想起单核细胞衍生的巨噬细胞（MDM）中潜伏的状态，其特征是整合的前病毒DNA与减少的病毒转录。这种静止状态与NF-κ B p65、RNA聚合酶II和p-TEF B募集到HIV-1启动子的减少以及启动子染色质维持在转录非允许状态有关。MDM向病毒潜伏期的转变由I型IFN信号传导介导，因为抑制I型IFN信号传导或阻断I型IFN可防止潜伏感染的建立。敲除研究表明，先天免疫信号分子线粒体抗病毒信号蛋白（MAVS）是过渡到潜伏期所必需的。最后，我们证明了病毒辅助蛋白Vpr在巨噬细胞中建立HIV-1潜伏期中的作用。我们的数据表明，HIV-1诱导的I型IFN产生是造成MDM中病毒潜伏期的原因，并确定了预防或消除这一重要HIV-1储存库的可能治疗靶点。确定了巨噬细胞诱导HIV-1潜伏期的分子机制。
Macrophages chronically infected with HIV‐1 serve as a reservoir that contributes to HIV‐1 persistence during antiretroviral therapy; however, the mechanisms governing the establishment and maintenance of this virus reservoir have not been fully elucidated. Here, we show that HIV‐1 enters a state reminiscent of latency in monocyte‐derived macrophages (MDMs), characterized by integrated proviral DNA with decreased viral transcription. This quiescent state is associated with decreased NF‐κB p65, RNA polymerase II, and p‐TEFb recruitment to the HIV‐1 promoter as well as maintenance of promoter chromatin in a transcriptionally nonpermissive state. MDM transition to viral latency is mediated by type I IFN signaling, as inhibiting type I IFN signaling or blocking type 1 IFN prevents the establishment of latent infection. Knockdown studies demonstrate that the innate immune signaling molecule mitochondrial antiviral signaling protein (MAVS) is required for the transition to latency. Finally, we demonstrate a role for the viral accessory protein Vpr in the establishment of HIV‐1 latency in macrophages. Our data indicate that HIV‐1‐induced type I IFN production is responsible for the establishment of viral latency in MDMs and identify possible therapeutic targets for the prevention or elimination of this important HIV‐1 reservoir. The molecular mechanisms by which macrophages induce HIV‐1 latency were identified.