AI Article Synopsis

  • The high mutation rate of RNA viruses allows them to adapt but also makes them prone to extinction, which is exploited by RNA mutagens for antiviral purposes.
  • This study used Venezuelan Equine Encephalitis Virus (VEEV) and the RNA mutagen β-d-N4-hydroxycytidine (NHC) to analyze how mutations affect virus replication and fitness.
  • Findings revealed that NHC induces mutations that negatively impact viral fitness, leading to a more diverse but less stable viral population, highlighting its potential as a treatment approach for alphaviruses.

Article Abstract

The high mutation rate of RNA viruses provides viral populations with the ability to adapt to new environments but also makes them vulnerable to extinction due to the deleterious effects of mutations, which is the conceptual basis for the antiviral activity of RNA mutagens. However, there are still gaps in the quantitative understanding of the dynamics between the mutations induced by an RNA mutagen and its effects on viral fitness. To address this, we used Venezuelan Equine Encephalitis Virus (VEEV) and the potent RNA mutagen β-d-N4-hydroxycytidine (NHC) as a model to analyze virus replication competency and mutation frequency following treatment in the total and replication-competent viral populations separately. We found that NHC induced transition mutations in a concentration dependent manner in the total population, while the replication-competent population maintained itself within an increased, yet narrow, mutation spectrum. The incorporation of NHC mainly happened during the positive sense RNA synthesis of VEEV. A growth kinetic analysis of VEEV population treated with NHC pointed to a lower but more diverse distribution in mutational fitness, demonstrating that NHC-induced mutations negatively and broadly affect the fitness of the virus. Together, our study provides mechanistic insight into how RNA mutagens affect viral population landscape and the potential of RNA mutagens as an antiviral strategy for alphaviruses.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11502654PMC
http://dx.doi.org/10.1038/s41598-024-76788-xDOI Listing

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