Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520.
Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2282-2289. doi: 10.1073/pnas.1819386116. Epub 2019 Jan 22.
HIV-1 integrates into the genome of target cells and establishes latency indefinitely. Understanding the molecular mechanism of HIV-1 latency maintenance is needed for therapeutic strategies to combat existing infection. In this study, we found an unexpected role for Apobec3A (apolipoprotein B MRNA editing enzyme catalytic subunit 3A, abbreviated "A3A") in maintaining the latency state within HIV-1-infected cells. Overexpression of A3A in latently infected cell lines led to lower reactivation, while knockdown or knockout of A3A led to increased spontaneous and inducible HIV-1 reactivation. A3A maintains HIV-1 latency by associating with proviral DNA at the 5' long terminal repeat region, recruiting KAP1 and HP1, and imposing repressive histone marks. We show that knockdown of A3A in latently infected human primary CD4 T cells enhanced HIV-1 reactivation. Collectively, we provide evidence and a mechanism by which A3A reinforces HIV-1 latency in infected CD4 T cells.
HIV-1 整合到靶细胞的基因组中，并无限期地建立潜伏期。为了寻找对抗现有感染的治疗策略，有必要了解 HIV-1 潜伏期维持的分子机制。在这项研究中，我们发现 Apobec3A（载脂蛋白 B mRNA 编辑酶催化亚基 3A，简称“A3A”）在维持 HIV-1 感染细胞的潜伏期状态方面具有意想不到的作用。在潜伏感染的细胞系中过表达 A3A 会导致较低的再激活，而敲低或敲除 A3A 会导致 HIV-1 的自发性和诱导性再激活增加。A3A 通过与前病毒 DNA 在 5'长末端重复区结合，招募 KAP1 和 HP1，并施加抑制性组蛋白标记来维持 HIV-1 的潜伏期。我们表明，在潜伏感染的人原代 CD4 T 细胞中敲低 A3A 会增强 HIV-1 的再激活。总之，我们提供了证据和机制，证明 A3A 增强了感染 CD4 T 细胞中的 HIV-1 潜伏期。
