Nikhil Prasad Fact checked by:Thailand Medical News Team Feb 28, 2025 4 hours, 55 minutes ago
Medical News: A new study conducted by researchers from Wuhan University in China has shed light on an essential molecular mechanism that helps hepatitis C virus (HCV) survive and replicate within human cells. The research focuses on a specific type of RNA modification known as 5-methylcytosine (m5C) and the role of the NSUN2 enzyme in this process. The findings provide crucial insights that could lead to the development of novel antiviral therapies targeting HCV.
Researchers Uncover a New Mechanism That Enhances Hepatitis C Virus Survival
HCV is a major global health concern, affecting nearly 57 million people worldwide and causing serious liver diseases such as cirrhosis and hepatocellular carcinoma. Despite the availability of antiviral drugs, challenges like drug resistance and reinfection continue to complicate treatment efforts. This
Medical News report explores the latest findings on how HCV manipulates host cell mechanisms to ensure its survival and replication.
Understanding the Role of m5C in HCV Replication
RNA modifications play a crucial role in regulating viral infections, and among them, m5C is one of the most recently discovered modifications. The study found that HCV, along with other flaviviruses like dengue and Zika, contains significant levels of m5C modifications. By analyzing viral RNA, researchers identified that m5C modifications in the HCV genome occur specifically at the C7525 site within the NS5A gene.
Further investigations revealed that HCV infection triggers the production of NSUN2, a key enzyme responsible for adding m5C modifications to RNA. The presence of m5C at this critical site enhances the stability of viral RNA, allowing the virus to replicate more efficiently and produce more infectious particles.
When the researchers disrupted NSUN2 production, they observed a significant decrease in HCV RNA stability, replication, and viral assembly, suggesting that NSUN2 is vital for the virus’s life cycle.
NSUN2 is a Key Target for New Antiviral Strategies
The research team also explored how HCV increases NSUN2 expression. They discovered that HCV infection activates a transcription factor known as E2F1, which binds to the NSUN2 gene and promotes its expression. This activation creates a positive feedback loop, further strengthening HCV replication. The findings indicate that blocking NSUN2 or disrupting its interaction with viral RNA could be a promising therapeutic strategy against HCV.
To validate their findings, the scientists introduced a mutation at the C7525 site, which prevents m5C modification. As a result, the mutated HCV strain exhibited lower RNA stability, reduced replication, and impaired viral assembly. This confirms the importance of m5C modification in maintaining HCV's infectious ability.
Potential for NSUN2 Inhibitors in Treating HCV
Given the critical role of NSUN2 in HCV replication, the researchers tested potential inhibitors of NSUN2, including small molecules like S
-adenosyl-L-homocysteine (SAH) and sinefungin. These compounds significantly reduced HCV replication in infected cells, particularly when used in combination with the FDA-approved antiviral drug sofosbuvir. This suggests that NSUN2 inhibitors could enhance the effectiveness of existing treatments and reduce the likelihood of drug resistance.
Furthermore, the study demonstrated that HCV infection not only modifies viral RNA but also increases global m5C modifications in host cellular RNA. This alteration affects the expression of immune-related genes, potentially helping the virus evade the immune response. However, when NSUN2 was knocked out, the expression of antiviral genes increased, further suppressing HCV replication.
Animal Model Confirms NSUN2 as a Target for HCV Therapy
To confirm their findings in a living system, the researchers used a genetically modified mouse model that allows HCV infection. In these mice, targeted knockdown of NSUN2 significantly reduced HCV RNA replication, viral protein production, and liver inflammation. This provides strong evidence that NSUN2-targeting therapies could be a viable approach for controlling HCV infection.
Conclusion
This groundbreaking study provides crucial insights into how HCV exploits the host's RNA modification system to sustain its replication and spread. The identification of NSUN2 as a key player in this process highlights a promising new target for antiviral therapies. By blocking NSUN2 activity or its interaction with viral RNA, future treatments could potentially limit HCV replication and improve patient outcomes. These findings pave the way for further research into developing NSUN2 inhibitors as an effective treatment for HCV and potentially other flavivirus infections.
The study findings were published in the peer reviewed journal: Genomics Proteomics & Bioinformatics.
https://academic.oup.com/gpb/advance-article/doi/10.1093/gpbjnl/qzaf008/8016383
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