Kuzmina Alona, Wattad Seraj, Murugavelu Praveenkumar, Amir Noa, Tickotsky Nili, Levin Liron, Taube Ran
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
Bioinformatics Core Facility, Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
mBio. 2025 Aug 13;16(8):e0055725. doi: 10.1128/mbio.00557-25. Epub 2025 Jul 3.
Antiretroviral therapy against the human immunodeficiency virus (HIV) has significantly prolonged the life span of people living with HIV, transforming viral infection into a latent condition that is characterized with undetectable viral loads. Yet, a complete cure of infection is out of reach, as transcriptionally silent but replication-competent proviruses persist in a long-lived reservoir that is resistant to therapy. The current work follows a genome-wide CRISPR knockout screen in human CD4 T cells and defines the activating transcription factor 1 (ATF1) as an activator of HIV gene transcription with elevated expression levels in cells that carry transcriptionally active provirus. Additional gain and loss-of-function experiments show that depletion of ATF1 promotes latency. ATF1 directly occupies the HIV promoter, where it regulates the recruitment of RNA Polymerase II and the levels of H3K9me3 histone repression mark. Genome-wide, ATF1 binds cellular gene promoters. Among its targets, ATF1 modulates the levels of CCR5 antisense lncRNA, thereby regulating the protein expression of the CCR5 HIV co-receptor. We conclude that ATF1 is an activator of gene transcription that dictates HIV gene expression via both direct and indirect mechanisms.
HIV persists in resting CD4 primary infected cells, forming a reservoir that is resistant to therapy, and thus a main barrier toward elimination of viral infection. An understanding of the mechanisms that control HIV gene expression and drive viral latency is therefore of high clinical importance. This study identifies activating transcription factor 1 (ATF1) as an activator of HIV gene expression. ATF1 binds the HIV promoter, where it modulates the occupancy of RNA Polymerase II and the levels of H3K9me3 histone repression mark. Genome-wide, ATF1 also occupies cellular promoters. One target of ATF1 is the antisense (AS) lncRNA. Through binding to CCR5-AS lncRNA, ATF1 induces CCR5 mRNA stability, thereby indirectly controlling HIV infection. Overall, we provide an additional understanding of the host transcription pathways that regulate HIV gene expression and potentially open new ways to manipulate its reservoir size.
抗人类免疫缺陷病毒（HIV）的抗逆转录病毒疗法显著延长了HIV感染者的寿命，将病毒感染转变为一种以病毒载量检测不到为特征的潜伏状态。然而，由于转录沉默但具有复制能力的原病毒持续存在于对治疗有抗性的长寿储存库中，感染的完全治愈仍遥不可及。当前的研究追踪了人类CD4 T细胞中的全基因组CRISPR敲除筛选，并将激活转录因子1（ATF1）定义为HIV基因转录的激活因子，其在携带转录活性原病毒的细胞中表达水平升高。额外的功能获得和丧失实验表明，ATF1的缺失促进潜伏。ATF1直接占据HIV启动子，在那里它调节RNA聚合酶II的募集以及H3K9me3组蛋白抑制标记的水平。在全基因组范围内，ATF1结合细胞基因启动子。在其靶标中，ATF1调节CCR5反义长链非编码RNA的水平，从而调节CCR5 HIV共受体的蛋白质表达。我们得出结论，ATF1是一种基因转录激活因子，通过直接和间接机制决定HIV基因表达。
HIV持续存在于静止的CD4原代感染细胞中，形成一个对治疗有抗性的储存库，因此是消除病毒感染的主要障碍。因此，了解控制HIV基因表达并驱动病毒潜伏的机制具有高度的临床重要性。本研究确定激活转录因子1（ATF1）为HIV基因表达的激活因子。ATF1结合HIV启动子，在那里它调节RNA聚合酶II的占据以及H3K9me3组蛋白抑制标记的水平。在全基因组范围内，ATF1也占据细胞启动子。ATF1的一个靶标是反义（AS）长链非编码RNA。通过与CCR5-AS长链非编码RNA结合，ATF1诱导CCR5 mRNA稳定性，从而间接控制HIV感染。总体而言，我们对调节HIV基因表达的宿主转录途径有了更多了解，并可能开辟操纵其储存库大小的新方法。
