Ribavirin causes error catastrophe during Hantaan virus replication

William E. Severson, Connie S. Schmaljohn, Ali Javadian, Colleen Jonsson

Research output: Contribution to journalArticle

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Abstract

Except for ribavirin, no other antiviral drugs for treating hantaviral diseases have been identified. It is well established that ribavirin will inhibit the production of infectious Hantaan virus (HTNV); however, its mechanism of action is unknown. To characterize the inhibitory effect of ribavirin on HTNV, the levels of viral RNAs, proteins, and infectious particles were measured for 3 days posttreatment of HTNV-infected Vero E6 cells. HTNV-infected cells treated with ribavirin showed a slight reduction in the levels of cRNA, viral RNA, and mRNA populations on the first day postinfection. The amount of cRNA and viral RNA increased to that observed for untreated HTNV-infected cells on day 2, whereas mRNA levels were more greatly reduced on days 2 and 3. Despite the finding of S-segment mRNA, albeit low, three of the viral proteins-nucleocapsid (N) protein and glycoproteins G1 and G2 - could not be detected by immunohistochemistry in ribavirin-treated cells. To test the hypothesis that these effects were caused by incorporation of ribavirin into nascent RNA and a resultant "error catastrophe" was occurring, we cloned and sequenced the S-segment cRNA/mRNA from ribavirin-treated or untreated cells from day 3. We found a high mutation frequency (9.5/1,000 nucleotides) in viral RNA synthesized in the presence of ribavirin. Hence, the transcripts produced in the presence of the drug were not functional. These results suggest that ribavirin's mechanism of action lies in challenging the fidelity of the hantavirus polymerase, which causes error catastrophe.

Original languageEnglish (US)
Pages (from-to)481-488
Number of pages8
JournalJournal of Virology
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2003

Fingerprint

Hantaan virus
Ribavirin
Virus Replication
virus replication
RNA
Viral RNA
Complementary RNA
cells
mechanism of action
Nucleocapsid Proteins
antiviral agents
Hantavirus
Messenger RNA
nucleocapsid
viral proteins
immunohistochemistry
glycoproteins
proteins
nucleotides
Vero Cells

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Ribavirin causes error catastrophe during Hantaan virus replication. / Severson, William E.; Schmaljohn, Connie S.; Javadian, Ali; Jonsson, Colleen.

In: Journal of Virology, Vol. 77, No. 1, 01.01.2003, p. 481-488.

Research output: Contribution to journalArticle

Severson, William E. ; Schmaljohn, Connie S. ; Javadian, Ali ; Jonsson, Colleen. / Ribavirin causes error catastrophe during Hantaan virus replication. In: Journal of Virology. 2003 ; Vol. 77, No. 1. pp. 481-488.
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