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Journal of Virology, May 2009, p. 4538-4547, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02280-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Reduced Ribavirin Antiviral Efficacy via Nucleoside Transporter-Mediated Drug Resistance{triangledown}

Kristie D. Ibarra and Julie K. Pfeiffer*

Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9048

Received 30 October 2008/ Accepted 17 February 2009

Treatment for hepatitis C virus infection currently consists of pegylated interferon and ribavirin (RBV), a nucleoside analog. Although RBV clearly plays a role in aiding the treatment response, its antiviral mechanism is unclear. Regardless of the specific mechanism of RBV, we hypothesize that differences in levels of cellular uptake of RBV may affect antiviral efficacy and treatment success and that cells may become RBV resistant through reduced uptake. We monitored RBV uptake in various cell lines and determined the effect of uptake capacity on viral replication. RBV-resistant cells demonstrated reduced RBV uptake and increased growth of a model RNA virus, poliovirus, in the presence of RBV. Overexpression of equilibrative nucleoside transporter 1 (ENT1) or concentrative nucleoside transporter 3 (CNT3) increased RBV uptake in RBV-sensitive cell lines and restored the uptake defect in most RBV-resistant cell lines. However, CNT3 is not expressed in Huh-7 liver cells, and inhibition of concentrative transport did not affect RBV uptake. Blocking equilibrative transport using the inhibitor nitrobenzylmercaptopurine riboside recapitulated the RBV-resistant phenotype in RBV-sensitive cell lines, with a reduction in RBV uptake and increased poliovirus growth. Taken together, these results indicate that RBV uptake is restricted primarily to ENT1 in the cell lines examined. Interestingly, some RBV-resistant cell lines may compensate for reduced ENT1-mediated nucleoside uptake by increasing the activity of an alternative nucleoside transporter, ENT2. It is possible that RBV uptake affects the antiviral treatment response, either through natural differences in patients or through acquired resistance.

* Corresponding author. Mailing address: Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9048. Phone: (214) 648-7319. Fax: (214) 648-5905. E-mail: Julie.Pfeiffer{at}UTSouthwestern.edu

{triangledown} Published ahead of print on 25 February 2009.

Journal of Virology, May 2009, p. 4538-4547, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02280-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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