Genetic and phenotypic changes to Venezuelan equine encephalitis virus following treatment with β-D-N4-hydroxycytidine, an RNA mutagen.

Autor: Alejandro B; Center for Predictive Medicine, University of Louisville, Louisville, KY, USA., Kim EJ; Center for Predictive Medicine, University of Louisville, Louisville, KY, USA., Hwang JY; Department of Medicine, University of Louisville, Louisville, KY, USA.; Brown Cancer Center Bioinformatics Core, University of Louisville, Louisville, KY, USA., Park JW; Department of Medicine, University of Louisville, Louisville, KY, USA.; Brown Cancer Center Bioinformatics Core, University of Louisville, Louisville, KY, USA., Smith M; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Louisville, Louisville, KY, USA., Chung D; Center for Predictive Medicine, University of Louisville, Louisville, KY, USA. hoon.chung@louisville.edu.; Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY, USA. hoon.chung@louisville.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Oct 25; Vol. 14 (1), pp. 25265. Date of Electronic Publication: 2024 Oct 25.
DOI: 10.1038/s41598-024-76788-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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