BRD9 functions as an HIV-1 latency regulatory factor

• 成果类型: Article
• 署名作者: Luk, Tsz-Yat; Yim, Lok-Yan; Zhou, Runhong; Mo, Yufei; Huang, Huarong; Zhao, Meiqing; Dai, Jie; Lau, Thomas Tsz-Kan; Huang, Xiner; Lui, Grace Chung-Yan; Yuen, Kwok-Yung; Chan, Jasper Fuk-Woo; Cheng, Alfred Sze-Lok; Chen, Zhiwei; Chu, Hin
• 署名单位: University of Hong Kong; University of Hong Kong; Chinese University of Hong Kong; University of Hong Kong; University of Hong Kong; Chinese University of Hong Kong; The University of Hong Kong Shenzhen Institute of Research & Innovation; University of Hong Kong
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13820
• DOI: 10.1073/pnas.2418467122
• 发表日期: 2025-05-27
• 关键词: phase 1/2; infection; inhibitor

摘要

A major challenge for HIV type 1 (HIV-1) cure is the presence of viral latent reservoirs. The Shock & Kill strategy involves the combined use of latency reversal agents (LRA) and antiretroviral treatment (ART) to reactivate HIV-1 latent reservoirs, followed by elimination of infected cells. However, current LRAs are insufficient in fully reactivating the latent reservoirs. Therefore, investigation on novel HIV-1 latency regulators will be crucial to the success of HIV-1 cure research. Here, we identify bromodomain-containing protein 9 (BRD9) as an HIV-1 latency regulator. BRD9 inhibition induces HIV-1 latency reactivation in T cell lines, human resting memory CD4+T cells, and PBMCs derived from people living with HIV-1 (PWH) on ART. BRD9 inhibition, gene depletion, and protein degradation consistently reactivate HIV-1 latency. Moreover, BRD9 inhibition synergizes with BRD4 inhibition in inducing HIV-1 production. Mechanistically, BRD9 binds to HIV-1 LTR promoter and competes with HIV-1 Tat protein for binding to the HIV-1 genome. Additionally, our integrated CUT&RUN DNA sequencing, transcriptomics, and pharmacological analysis revealed downstream host targets of BRD9, including ATAD2 and MTHFD2, that modulate HIV-1 latency.