Nucleolar protein NOP2/NSUN1 suppresses HIV-1 transcription and promotes viral latency by competing with Tat for TAR binding and methylation

• DOI: 10.1371/journal.ppat.1008430
• Publication Date: 2020-03-16T17:31:48Z
• Authors: Weili Kong; Ayan Biswas; Dawei Zhou; Guillaume Fiches; Koh Fujinaga; Netty Santoso; Jian Zhu
• Keywords: 0301 basic medicine; tRNA Methyltransferases; Transcription, Genetic; QH301-705.5; Nuclear Proteins; RC581-607; DNA Methylation; Virus Latency; 3. Good health; Jurkat Cells; 03 medical and health sciences; DNA, Viral; HIV-1; Humans; RNA, Viral; tat Gene Products, Human Immunodeficiency Virus; Immunologic diseases. Allergy; Biology (General); Research Article; HIV Long Terminal Repeat

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.