ORC1 enhances repressive epigenetic modifications on HIV-1 LTR to promote HIV-1 latency

作者：Mo Zhou, Tao Yang, Ming Yuan, Xinyu Li, Jieyi Deng, Shiyu Wu, Zhihan Zhong, Yingtong Lin, Wanying Zhang, Baijin Xia, Yating Wu, Lilin Wang, Tao Chen, Ruxin Liu, Ting Pan, Xiancai Ma, Linghua Li, Bingfeng Liu, Hui Zhang · 发表于：Journal of Virology · 年份：2024 · DOI：10.1128/jvi.00035-24 · 被引用次数：7 · 研究领域：HIV Research and Treatment、DNA Repair Mechanisms、HIV/AIDS drug development and treatment

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) reservoir consists of latently infected cells which present a major obstacle to achieving a functional cure for HIV-1. The formation and maintenance of HIV-1 latency have been extensively studied, and latency-reversing agents (LRAs) that can reactivate latent HIV-1 by targeting the involved host factors are developed; however, their clinical efficacies remain unsatisfactory. Therefore, it is imperative to identify novel targets for more potential candidates or better combinations for LRAs. In this study, we utilized CRISPR affinity purification in situ of regulatory elements system to screen for host factors associated with the HIV-1 long terminal repeat region that could potentially be involved in HIV-1 latency. We successfully identified that origin recognition complex 1 (ORC1), the largest subunit of the origin recognition complex, contributes to HIV-1 latency in addition to its function in DNA replication initiation. Notably, ORC1 is enriched on the HIV-1 promoter and recruits a series of repressive epigenetic elements, including DNMT1 and HDAC1/2, and histone modifiers, such as H3K9me3 and H3K27me3, thereby facilitating the establishment and maintenance of HIV-1 latency. Moreover, the reactivation of latent HIV-1 through ORC1 depletion has been confirmed across various latency cell models and primary CD4 + T cells from people living with HIV-1. Additionally, we comprehensively validated the properties of liquid-liq...