Department of Pathology, Ohio State University College of Medicine, Columbus, Ohio, United States of America.
Gladstone Institute of Virology and Immunology, University of California, San Francisco, California, United States of America.
PLoS Pathog. 2020 Mar 16;16(3):e1008430. doi: 10.1371/journal.ppat.1008430. eCollection 2020 Mar.
Recent efforts have been paid to identify previously unrecognized HIV-1 latency-promoting genes (LPGs) that can potentially be targeted for eradication of HIV-1 latent reservoirs. From our earlier orthologous RNAi screens of host factors regulating HIV-1 replication, we identified that the nucleolar protein NOP2/NSUN1, a m5C RNA methyltransferase (MTase), is an HIV-1 restriction factor. Loss- and gain-of-function analyses confirmed that NOP2 restricts HIV-1 replication. Depletion of NOP2 promotes the reactivation of latently infected HIV-1 proviruses in multiple cell lines as well as primary CD4+ T cells, alone or in combination with latency-reversing agents (LRAs). Mechanistically, NOP2 associates with HIV-1 5' LTR, interacts with HIV-1 TAR RNA by competing with HIV-1 Tat protein, as well as contributes to TAR m5C methylation. RNA MTase catalytic domain (MTD) of NOP2 mediates its competition with Tat and binding with TAR. Overall, these findings verified that NOP2 suppresses HIV-1 transcription and promotes viral latency.
最近，人们努力识别以前未被识别的 HIV-1 潜伏促进基因 (LPGs)，这些基因可能成为根除 HIV-1 潜伏储库的潜在靶点。从我们之前对调节 HIV-1 复制的宿主因素的同源 RNAi 筛选中，我们发现核仁蛋白 NOP2/NSUN1，一种 m5C RNA 甲基转移酶 (MTase)，是 HIV-1 的限制因子。缺失和功能获得分析证实，NOP2 限制了 HIV-1 的复制。耗尽 NOP2 可促进潜伏感染的 HIV-1 前病毒在多种细胞系以及原代 CD4+ T 细胞中的重新激活，单独或与潜伏逆转剂 (LRAs) 联合使用。从机制上讲，NOP2 与 HIV-1 5' LTR 结合，通过与 HIV-1 Tat 蛋白竞争与 HIV-1 TAR RNA 相互作用，并有助于 TAR m5C 甲基化。NOP2 的 RNA MTase 催化结构域 (MTD) 介导其与 Tat 的竞争和与 TAR 的结合。总的来说，这些发现证实了 NOP2 抑制 HIV-1 转录并促进病毒潜伏。
