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Journal of Virology, May 2005, p. 6291-6298, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6291-6298.2005

New Antiviral Pathway That Mediates Hepatitis C Virus Replicon Interferon Sensitivity through ADAR1

Deborah R. Taylor,* Montserrat Puig, Miriam E. R. Darnell, Kathleen Mihalik, and Stephen M. Feinstone

Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Received 25 May 2004/ Accepted 1 January 2005

While many clinical hepatitis C virus (HCV) infections are resistant to alpha interferon (IFN-{alpha}) therapy, subgenomic in vitro self-replicating HCV RNAs (HCV replicons) are characterized by marked IFN-{alpha} sensitivity. IFN-{alpha} treatment of replicon-containing cells results in a rapid loss of viral RNA via translation inhibition through double-stranded RNA-activated protein kinase (PKR) and also through a new pathway involving RNA editing by an adenosine deaminase that acts on double-stranded RNA (ADAR1). More than 200 genes are induced by IFN-{alpha}, and yet only a few are attributed with an antiviral role. We show that inhibition of both PKR and ADAR1 by the addition of adenovirus-associated RNA stimulates replicon expression and reduces the amount of inosine recovered from RNA in replicon cells. Small inhibitory RNA, specific for ADAR1, stimulated the replicon 40-fold, indicating that ADAR1 has a role in limiting replication of the viral RNA. This is the first report of ADAR's involvement in a potent antiviral pathway and its action to specifically eliminate HCV RNA through adenosine to inosine editing. These results may explain successful HCV replicon clearance by IFN-{alpha} in vitro and may provide a promising new therapeutic strategy for HCV as well as other viral infections.

* Corresponding author. Mailing address: CBER/FDA, HFM-448, 8800 Rockville Pike, Bethesda, MD 20892. Phone: (301) 827-3660. Fax: (301) 496-1810. E-mail: taylord{at}cber.fda.gov.

Journal of Virology, May 2005, p. 6291-6298, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6291-6298.2005




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