Mathematical modeling of subgenomic hepatitis C virus replication in Huh-7 cells.

Abstract:

: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 10(3) 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 approximately 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.

journal_name

J Virol

journal_title

Journal of virology

authors

Dahari H,Ribeiro RM,Rice CM,Perelson AS

doi

10.1128/JVI.01304-06

subject

Has Abstract

pub_date

2007-01-01 00:00:00

pages

750-60

issue

2

eissn

0022-538X

issn

1098-5514

pii

JVI.01304-06

journal_volume

81

pub_type

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