NSUN2-mediated m5C modification of HIV-1 RNA enables evasion of RIG‑I‑dependent innate immunity.

Authors

Yuebo Xu, Mingyang Li, Yingying Song, Weili Kong, Jingjing Song, Jiali Zhang, Xinmu Xu, Haoyu Ma, Shun Yu, Shuliang Chen, Cong Zeng

Published in

PLoS pathogens. Volume 22. Issue 9. Pages e1014611. Epub Sep 25, 2026.

Abstract

Recently, 5-methylcytosine (m5C) modification has been identified in HIV-1 genomic RNA. However, the functional role of this RNA modification in the antiviral innate immune response remains unclear. Here, we demonstrate that m5C modification of HIV-1 genomic RNA enables the virus to evade the type I interferon (IFN-I)-mediated antiviral response, thereby promoting viral replication. Depletion of NSUN2 in viral-producing cells significantly reduced m5C modification of HIV-1 RNA, leading to progeny viruses that are more susceptible to innate immune detection and consequently displaying attenuated replication. Furthermore, in vitro-transcribed m5C-modified RNA exhibited a reduced ability to induce IFN-I production relative to unmodified RNA. Additionally, m5C-modified RNA displayed markedly impaired binding to RIG-I compared with unmodified RNA. Collectively, our findings reveal that HIV-1 utilizes m5C modification of viral genomic RNA as a strategy to escape RIG-I-mediated immune recognition, thereby facilitating efficient viral replication.

PMID:
42789514
Bibliographic data and abstract were imported from PubMed on 26 Sep 2026.

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