Abstract
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.
Highlights
Human immunodeficiency virus (HIV-1) pandemic remains a concern of global public health
We confirmed that NOP2, NSUN m5C RNA MTase is a novel host factor suppressing HIV-1 transcription
To validate NOP2 as an HIV-1 host restriction factor identified from RNAi screens, we depleted the endogenous NOP2 in MAGI-HeLa cells using its siRNA or non-target siRNA, whose knockdown efficiency was confirmed by immunoblotting with an antiNOP2 antibody (Fig 1B)
Summary
Human immunodeficiency virus (HIV-1) pandemic remains a concern of global public health. The current combination antiretroviral therapy (cART) is potent to inhibit HIV-1 replication and reduce viral load below the detection limit, it cannot eliminate residual viremia in treated HIV+ individuals and new HIV-1infections still occur with a static rate. These HIV+ individuals have to use cART drugs for the rest of their life, while the drug resistance may develop due to the mutations of HIV-1 genomes [1]. The improved understanding of host factors regulating HIV-1 replication, especially those silencing HIV-1 viral transcription and promoting its latency, will help us to develop the more effective LRAs and other therapeutic reagents that can be applied for curing HIV
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