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

被引:82
作者
Dahari, Harel
Ribeiro, Ruy M.
Rice, Charles M.
Perelson, Alan S.
机构
[1] Los Alamos Natl Lab, Los Alamos, NM 87545 USA
[2] Rockefeller Univ, Ctr Study Hepatitis C, Lab Virol & Infect Dis, New York, NY 10021 USA
关键词
D O I
10.1128/JVI.01304-06
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 similar to 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.
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页码:750 / 760
页数:11
相关论文
共 65 条
[11]   Dynamics of hepatitis C virus replication in human liver [J].
Chang, M ;
Williams, O ;
Mittler, J ;
Quintanilla, A ;
Carithers, RL ;
Perkins, J ;
Corey, L ;
Gretch, DR .
AMERICAN JOURNAL OF PATHOLOGY, 2003, 163 (02) :433-444
[12]   REPLICATION STRATEGY OF KUNJIN VIRUS - EVIDENCE FOR RECYCLING ROLE OF REPLICATIVE FORM RNA AS TEMPLATE IN SEMICONSERVATIVE AND ASYMMETRIC REPLICATION [J].
CHU, PWG ;
WESTAWAY, EG .
VIROLOGY, 1985, 140 (01) :68-79
[13]   IDENTIFICATION AND CHARACTERIZATION OF TYPE-2 DENGUE VIRUS REPLICATIVE INTERMEDIATE AND REPLICATIVE FORM RNAS [J].
CLEAVES, GR ;
RYAN, TE ;
SCHLESINGER, RW .
VIROLOGY, 1981, 111 (01) :73-83
[14]   Mathematical modeling of primary hepatitis C infection: Noncytolytic clearance and early blockage of virion production [J].
Dahari, H ;
Major, M ;
Zhang, XN ;
Mihalik, K ;
Rice, CM ;
Perelson, AS ;
Feinstone, SM ;
Neumann, AU .
GASTROENTEROLOGY, 2005, 128 (04) :1056-1066
[15]   Second hepatitis C replication compartment indicated by viral dynamics during liver transplantation [J].
Dahari, H ;
Feliu, A ;
Garcia-Retortillo, M ;
Forns, X ;
Neumann, AU .
JOURNAL OF HEPATOLOGY, 2005, 42 (04) :491-498
[16]   Modelling how ribavirin improves interferon response rates in hepatitis C virus infection [J].
Dixit, NM ;
Layden-Almer, JE ;
Layden, TJ ;
Perelson, AS .
NATURE, 2004, 432 (7019) :922-924
[17]   Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex [J].
Egger, D ;
Wölk, B ;
Gosert, R ;
Bianchi, L ;
Blum, HE ;
Moradpour, D ;
Bienz, K .
JOURNAL OF VIROLOGY, 2002, 76 (12) :5974-5984
[18]   THE HYPERCYCLE - COUPLING OF RNA AND PROTEIN-BIOSYNTHESIS IN THE INFECTION CYCLE OF AN RNA BACTERIOPHAGE [J].
EIGEN, M ;
BIEBRICHER, CK ;
GEBINOGA, M ;
GARDINER, WC .
BIOCHEMISTRY, 1991, 30 (46) :11005-11018
[19]   Kissing-loop interaction in the 3′ end of the hepatitis C virus genome essential for RNA replication [J].
Friebe, P ;
Boudet, J ;
Simorre, JP ;
Bartenschlager, R .
JOURNAL OF VIROLOGY, 2005, 79 (01) :380-392
[20]   Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. [J].
Fried, MW ;
Shiffman, ML ;
Reddy, KR ;
Smith, C ;
Marinos, G ;
Goncales, FL ;
Haussinger, D ;
Diago, M ;
Carosi, G ;
Dhumeaux, D ;
Craxi, A ;
Lin, A ;
Hoffman, J ;
Yu, J .
NEW ENGLAND JOURNAL OF MEDICINE, 2002, 347 (13) :975-982