Wang Xinyu, Xue Yuhua, Li Lin, Song Jinwen, Jia Lei, Li Xu, Fan Miao, Lu Lu, Su Wen, Han Jingwan, Lin Dandan, Liu Rongdiao, Gao Xiang, Guo Yafei, Xiang Zixun, Chen Chunjing, Wan Linyu, Chong Huihui, He Yuxian, Wang Fusheng, Yao Kaihu, Zhou Qiang, Yu Dan
Laboratory of Infection and Microbiology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Key Laboratory of Major Diseases in Children, Ministry of Education, National Center for Children's Health, Beijing, China.
State Key Laboratory of Vaccines for Infectious Diseases, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiang An Biomedicine Laboratory, Affiliated Xiamen Eye Center, Xiamen University, Xiamen, China.
Nat Commun. 2025 May 15;16(1):4529. doi: 10.1038/s41467-025-59578-5.
Latent HIV-1 presents a formidable challenge for viral eradication. HIV-1 transcription and latency reversal require interactions between the viral promoter and host proteins. Here, we perform the dCas9-targeted locus-specific protein analysis and discover the interaction of human arginine methyltransferase 3 (PRMT3) with the HIV-1 promoter. This interaction reverses latency in cell line models and primary cells from latently infected persons by increasing the levels of H4R3Me2a and transcription factor P-TEFb at the viral promoter. PRMT3 is found to promote chromatin accessibility and transcription of HIV-1 and a small subset of host genes in regions harboring the classical recognition motif for another transcription factor TEAD4. This motif attracts TEAD4 and PRMT3 to the viral promoter to synergistically activate transcription. Physical interactions among PRMT3, P-TEFb, and TEAD4 exist, which may help form a transcriptional hub at the viral promoter. Our study reveals the potential of targeting these hub proteins to eradicate latent HIV-1.
潜伏的HIV-1对病毒根除构成了巨大挑战。HIV-1转录和潜伏期逆转需要病毒启动子与宿主蛋白之间的相互作用。在这里，我们进行了dCas9靶向的位点特异性蛋白质分析，并发现了人类精氨酸甲基转移酶3（PRMT3）与HIV-1启动子的相互作用。这种相互作用通过增加病毒启动子处H4R3Me2a和转录因子P-TEFb的水平，逆转了细胞系模型和潜伏感染个体原代细胞中的潜伏期。发现PRMT3可促进HIV-1以及另一个转录因子TEAD4的经典识别基序所在区域中一小部分宿主基因的染色质可及性和转录。该基序将TEAD4和PRMT3吸引到病毒启动子上，协同激活转录。PRMT3、P-TEFb和TEAD4之间存在物理相互作用，这可能有助于在病毒启动子处形成转录中心。我们的研究揭示了靶向这些中心蛋白以根除潜伏HIV-1的潜力。
