NSUN2-mediated m5C modification of HIV-1 RNA enables evasion of RIG‑I‑dependent innate immunity
- 1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
- 2Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, Hubei, China
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. Author summary: HIV-1 remains a major global health challenge, in part because the virus has evolved clever ways to avoid being detected by the human immune system. In our study, we set out to understand how HIV-1 evades the body’s first line of defense, known as innate immunity. We discovered that HIV-1 hijacks a human protein called NSUN2 to add a chemical mark called m5C to its own genomic RNA. This mark hides the viral RNA from RIG-I, which normally recognizes foreign RNA and triggers an antiviral response. By masking itself this way, HIV-1 can replicate more efficiently and establish infection. Our findings reveal a new strategy HIV-1 uses to evade the immune system, linking RNA chemical modifications to viral escape. This knowledge not only deepens our understanding of how HIV-1 survives in the body but also points to potential new targets for developing treatments that could help the immune system recognize and fight the virus.
Related
- Limited cross strain CMV protection by a bivalent (gB/pp65) vaccine is based on an impaired gB antibody response and evasion of pp65 cell mediated immunity
- NOD2 restrains probiotic-mediated TLR2-dependent antitumor immunity
- METTL3-mediated m6A modification alleviates skeletal muscle atrophy in ALS by regulating ACSL1-dependent triglyceride metabolism
- HERC5-mediated co-translational ISGylation in innate immunity: molecular mechanisms, context-dependent regulation, and therapeutic potential
- Porcine Reproductive and Respiratory Syndrome Virus: Adaptive Immunity, Immune Evasion and Emerging Strategies for Disease Control.
BibTeX
@article{xu2026nsun2mediated,
title = {{NSUN2-mediated m5C modification of HIV-1 RNA enables evasion of RIG‑I‑dependent innate immunity}},
author = {Yuebo Xu and Mingyang Li and Yingying Song and Weili Kong and Jingjing Song and Jiali Zhang and Xinmu Xu and Haoyu Ma and Shun Yu and Shuliang Chen and Cong Zeng},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014611},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014611},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - NSUN2-mediated m5C modification of HIV-1 RNA enables evasion of RIG‑I‑dependent innate immunity
AU - Yuebo Xu
AU - Mingyang Li
AU - Yingying Song
AU - Weili Kong
AU - Jingjing Song
AU - Jiali Zhang
AU - Xinmu Xu
AU - Haoyu Ma
AU - Shun Yu
AU - Shuliang Chen
AU - Cong Zeng
PY - 2026
DA - 2026/09/25
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014611
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014611
AB - 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. Author summary: HIV-1 remains a major global health challenge, in part because the virus has evolved clever ways to avoid being detected by the human immune system. In our study, we set out to understand how HIV-1 evades the body’s first line of defense, known as innate immunity. We discovered that HIV-1 hijacks a human protein called NSUN2 to add a chemical mark called m5C to its own genomic RNA. This mark hides the viral RNA from RIG-I, which normally recognizes foreign RNA and triggers an antiviral response. By masking itself this way, HIV-1 can replicate more efficiently and establish infection. Our findings reveal a new strategy HIV-1 uses to evade the immune system, linking RNA chemical modifications to viral escape. This knowledge not only deepens our understanding of how HIV-1 survives in the body but also points to potential new targets for developing treatments that could help the immune system recognize and fight the virus.
SN - 1553-7374
ER -