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Investigating the Influence of Ribavirin on Human Respiratory Syncytial Virus RNA Synthesis by Using a High-Resolution Transcriptome Sequencing Approach

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)4876-4888
Number of pages13
JournalJournal of Virology
Volume90
Issue number10
Early online date9 Dec 2015
DOIs
DateAccepted/In press - 18 Nov 2015
DateE-pub ahead of print - 9 Dec 2015
DatePublished (current) - 15 May 2016

Abstract

UNLABELLED: Human respiratory syncytial virus (HRSV) is a major cause of serious respiratory tract infection. Treatment options include administration of ribavirin, a purine analog, although the mechanism of its anti-HRSV activity is unknown. We used transcriptome sequencing (RNA-seq) to investigate the genome mutation frequency and viral mRNA accumulation in HRSV-infected cells that were left untreated or treated with ribavirin. In the absence of ribavirin, HRSV-specific transcripts accounted for up to one-third of total RNA reads from the infected-cell RNA population. Ribavirin treatment resulted in a >90% reduction in abundance of viral mRNA reads, while at the same time no such reduction was detected for the abundance of cellular transcripts. The presented data reveal that ribavirin significantly increases the frequency of HRSV-specific RNA mutations, suggesting a direct influence on the fidelity of the HRSV polymerase. The presented data show that transitions and transversions occur during HRSV replication and that these changes occur in hot spots along the HRSV genome. Examination of nucleotide substitution rates in the viral genome indicated an increase in the frequency of transition but not transversion mutations in the presence of ribavirin. In addition, our data indicate that in the continuous cell types used and at the time points analyzed, the abundances of some HRSV mRNAs do not reflect the order in which the mRNAs are transcribed.

IMPORTANCE: Human respiratory syncytial virus (HRSV) is a major pediatric pathogen. Ribavirin can be used in children who are extremely ill to reduce the amount of virus and to lower the burden of disease. Ribavirin is used as an experimental therapy with other viruses. The mechanism of action of ribavirin against HRSV is not well understood, although it is thought to increase the mutation rate of the viral polymerase during replication. To investigate this hypothesis, we used a high-resolution approach that allowed us to determine the genetic sequence of the virus to a great depth of coverage. We found that ribavirin did not cause a detectable change in the relative amounts of viral mRNA transcripts. However, we found that ribavirin treatment did indeed cause an increase in the number of mutations, which was associated with a decrease in virus production.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via the American Society for Microbiology at https://doi.org/10.1128/JVI.02349-15 . Please refer to any applicable terms of use of the publisher.

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