BRD9 functions as an HIV-1 latency regulatory factor
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Tsz-Yat Luk
AIDS Institute, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Lok-Yan Yim
AIDS Institute, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Runhong Zhou
AIDS Institute, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Yufei Mo
AIDS Institute, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Huarong Huang
AIDS Institute, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Meiqing Zhao
AIDS Institute, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Jie Dai
State Key Laboratory of Green Papermaking and Resource Recycling, School of Environmental Science and Engineering
Thomas Tsz-Kan Lau
AIDS Institute, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Xiner Huang
Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Grace Chung-Yan Lui
Division of Infectious Diseases, Department of Medicine and Therapeutics, The Chinese University of Hong Kong
Kwok-Yung Yuen
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Jasper Fuk-Woo Chan
Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Alfred Sze-Lok Cheng
School of Biomedical Sciences, The Chinese University of Hong Kong
Zhiwei Chen
Hin Chu
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong