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Journal of Virology, July 2009, p. 6383-6390, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02612-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Modeling Subgenomic Hepatitis C Virus RNA Kinetics during Treatment with Alpha Interferon {triangledown}

Harel Dahari,1,{dagger} Bruno Sainz Jr.,1,{dagger} Alan S. Perelson,3 and Susan L. Uprichard1,2*

Department of Medicine,1 Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois 60612,2 Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico 875453

Received 17 December 2008/ Accepted 6 April 2009

Although replicons have been used to demonstrate hepatitis C virus (HCV) inhibition by alpha interferon (IFN-{alpha}), the detailed inhibition kinetics required to mathematically model HCV RNA decline have been lacking. Therefore, we measured genotype 1b subgenomic replicon (sg1b) RNA levels under various IFN-{alpha} concentrations to assess the inhibition kinetics of intracellular HCV RNA. During nine days of IFN-{alpha} treatment, sg1b RNA decreased in a biphasic, dose-dependent manner. Using frequent measurements to dissect these phases during IFN-{alpha} treatments of 100 and 250 U/ml revealed that the first-phase sg1b RNA decline began ~12 h posttreatment, continued for 2 to 4 days, and then exhibited a distinct flat or slower second phase. Based on these data, we developed a mathematical model of IFN-{alpha}-induced intracellular sg1b RNA decline, and we show that the mechanism(s) mediating IFN-{alpha} inhibition of HCV acts primarily by reducing sg1b RNA amplification, with an additional effect on HCV RNA stability/degradation detectable at a dose of 250 U/ml IFN-{alpha}. While the extremely slow or flat second phase of viral RNA inhibition observed in vitro, in which there is little or no cell death, supports the in vivo modeling prediction that the more profound second-phase decline observed in IFN-{alpha}-treated patients reflects immune-mediated death/loss of productively infected cells, the second-phase decline in viral RNA with a dose of 250 U/ml IFN-{alpha} suggests that a further inhibition of intracellular HCV RNA levels may contribute as well. As such, dissection of HCV IFN-{alpha} inhibition kinetics in vitro has brought us closer to understanding the mechanism(s) by which IFN-{alpha} may be inhibiting HCV in vivo.

* Corresponding author. Mailing address: Department of Medicine, Section of Hepatology, The University of Illinois at Chicago, 840 S. Wood Street MC787, Chicago, IL 60612. Phone: (312) 355-3784. Fax: (312) 413-0342. E-mail: sluprich{at}uic.edu

{triangledown} Published ahead of print on 15 April 2009.

{dagger} B.S. and H.D. contributed equally to this study.

Journal of Virology, July 2009, p. 6383-6390, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02612-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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