Document Detail


Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3' nontranslated region are essential for virus replication in vivo.
MedLine Citation:
PMID:  10644379     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hepatitis C virus (HCV) infection is a widespread major human health concern. Significant obstacles in the study of this virus include the absence of a reliable tissue culture system and a small-animal model. Recently, we constructed full-length HCV cDNA clones and successfully initiated HCV infection in two chimpanzees by intrahepatic injection of in vitro-transcribed RNA (A. A. Kolykhalov et al., Science 277:570-574, 1997). In order to validate potential targets for development of anti-HCV therapeutics, we constructed six mutant derivatives of this prototype infectious clone. Four clones contained point mutations ablating the activity of the NS2-3 protease, the NS3-4A serine protease, the NS3 NTPase/helicase, and the NS5B polymerase. Two additional clones contained deletions encompassing all or part of the highly conserved 98-base sequence at the 3' terminus of the HCV genome RNA. The RNA transcript from each of the six clones was injected intrahepatically into a chimpanzee. No signs of HCV infection were detected in the 8 months following the injection. Inoculation of the same animal with nonmutant RNA transcripts resulted in productive HCV infection, as evidenced by viremia, elevated serum alanine aminotransferase, and HCV-specific seroconversion. These data suggest that these four HCV-encoded enzymatic activities and the conserved 3' terminal RNA element are essential for productive replication in vivo.
Authors:
A A Kolykhalov; K Mihalik; S M Feinstone; C M Rice
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of virology     Volume:  74     ISSN:  0022-538X     ISO Abbreviation:  J. Virol.     Publication Date:  2000 Feb 
Date Detail:
Created Date:  2000-03-02     Completed Date:  2000-03-02     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2046-51     Citation Subset:  IM    
Affiliation:
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110-1093, USA.
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MeSH Terms
Descriptor/Qualifier:
3' Untranslated Regions*
Cysteine Endopeptidases / genetics,  metabolism
DNA, Complementary
DNA, Viral
Enzyme Precursors / genetics,  metabolism
Hepacivirus / enzymology*,  genetics,  physiology*
Humans
Mutagenesis
RNA Replicase / genetics,  metabolism
RNA, Viral / physiology*
Serine Endopeptidases / genetics,  metabolism
Viral Nonstructural Proteins / genetics,  metabolism
Virus Replication*
Grant Support
ID/Acronym/Agency:
AI40034/AI/NIAID NIH HHS; CA57973/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/3' Untranslated Regions; 0/DNA, Complementary; 0/DNA, Viral; 0/Enzyme Precursors; 0/NS-5 protein, hepatitis C virus; 0/NS3 protein, hepatitis C virus; 0/NS4 protein, hepatitis C virus; 0/RNA, Viral; 0/Viral Nonstructural Proteins; EC 2.7.7.48/RNA Replicase; EC 3.4.21.-/Serine Endopeptidases; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.-/NS2-3 protease
Comments/Corrections

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