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Journal of Virology, January 2007, p. 750-760, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01304-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mathematical Modeling of Subgenomic Hepatitis C Virus Replication in Huh-7 Cells{triangledown}

Harel Dahari,1 Ruy M. Ribeiro,1 Charles M. Rice,2 and Alan S. Perelson1*

Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, New Mexico 87545,1 Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 100212

Received 20 June 2006/ Accepted 3 October 2006

Cell-based hepatitis C virus (HCV) replicon systems have provided a means for understanding HCV replication mechanisms and for testing new antiviral agents. We describe here a mathematical model of HCV replication that assumes that the translation of the HCV polyprotein occurs in the cytoplasm, that HCV RNA synthesis occurs in vesicular-membrane structures, and that the strategy of replication involves a double-stranded RNA intermediate. Our results shed light on the intracellular dynamics of subgenomic HCV RNA replication from transfection to steady state within Huh-7 cells. We predict the following: (i) about 6 x 103 ribosomes are involved in generating millions of HCV NS5B-polymerase molecules in a Huh-7 cell, (ii) the observed 10:1 asymmetry of plus- to minus-strand RNA levels can be explained by a higher-affinity (200-fold) interaction of HCV NS5B polymerase-containing replication complexes with HCV minus-strand RNA over HCV plus-strand RNA in order to initiate synthesis, (iii) the latter higher affinity can also account for the observed ~6:1 plus-strand/minus-strand ratio in vesicular-membrane structures, and (iv) the introduction of higher numbers of HCV plus-strand RNA by transfection leads to faster attainment of steady-state but does not change the steady-state HCV RNA level. Fully permissive HCV replication systems have been developed, and the model presented here is a first step toward building a comprehensive model for complete HCV replication. Moreover, the model can serve as an important tool in understanding HCV replication mechanisms and should prove useful in designing and evaluating new antivirals against HCV.

* Corresponding author. Mailing address: Theoretical Biology and Biophysics, MS-K710, T-10, Los Alamos National Laboratory, NM 87545. Phone: (505) 667-6829. Fax: (505) 665-3493. E-mail: asp{at}lanl.gov.

{triangledown} Published ahead of print on 11 October 2006.

Journal of Virology, January 2007, p. 750-760, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01304-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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