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Gastroenterology. 2005 Feb;128(2):449-62.

La protein is a potent regulator of replication of hepatitis C virus in patients with chronic hepatitis C through internal ribosomal entry site-directed translation.

Author information

1
Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.

Abstract

BACKGROUND AND AIMS:

Translation of hepatitis C virus is an essential step of viral replication and is mediated by an internal ribosome entry site. We previously reported that the hepatitis C virus internal ribosome entry site is most active during the synthetic (S) or mitotic (M) phases and lowest during quiescent (G 0 ) phase. Here, we investigated host factors responsible for the regulation of the hepatitis C virus internal ribosome entry site.

METHODS:

We synchronized the cell-cycle progression and evaluated gene-expression dynamics of host factors and kinetics of hepatitis C virus internal ribosome entry site activity in cells at various points during the cell cycle by using a complementary DNA microarray. We also validated the significance of identified host factors on hepatitis C virus replication in vivo.

RESULTS:

Hepatitis C virus internal ribosome entry site activity correlated with a gene cluster induced in the S and G 2 /M phases. It is interesting to note that most initiation factors known to bind or interact with the hepatitis C virus internal ribosome entry site [poly(rC)-binding protein 2, polypyrimidine tract binding protein, eukaryotic initiation factor 3, eukaryotic initiation factor 2gamma, eukaryotic initiation factor 2beta, La protein, and heterogenous nuclear ribonucleoprotein L] were induced during the S and G 2 /M phases. Expression of La protein, polypyrimidine tract binding protein, and eukaryotic initiation factor 3 (p116, p170) were predominantly repressed in G 0 phase and induced in S and G 2 /M phases. Suppression or overexpression of La protein and polypyrimidine tract binding protein in RCF-26 significantly changed hepatitis C virus internal ribosome entry site activity. In the livers of patients with chronic hepatitis C, expression of La protein was significantly increased and correlated with the amount of hepatitis C virus RNA.

CONCLUSIONS:

Hepatitis C virus uses host factors induced during cell division but not during quiescence for replication. Of these, La protein is a potent regulator and enhances hepatitis C virus replication in regenerating hepatocytes in patients with chronic hepatitis C.

PMID:
15685555
DOI:
10.1053/j.gastro.2004.11.064
[Indexed for MEDLINE]

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