Arch Virol (2003) 148: 1247–1267
The proteins of the Hepatitis C virus: Their features
and interactions with intracellular protein phosphorylation
J. Schulze zur Wiesch
, H. Schmitz
, E. Borowski
, and P. Borowski
Partners AIDS Research Center, Massachusetts General Hospital,
Charlestown, Massachusetts, U.S.A.
Bernhard-Nocht-Institut f¨ur Tropenmedizin, Abteilung f¨ur Virologie,
Received March 7, 2003; accepted March 18, 2003
Published online June 2, 2003
Summary. Chronic infection with Hepatitis C virus (HCV) often results in cir-
rhosis and enhances the probability of developing hepatocellular carcinoma (HCC).
The underlying mechanisms that lead to malignant transformation of infected
cells, however, remain unclear. Observations made with isolated HCV antigens
and/or with HCV subgenomic replicon systems demonstrated that the products
encoded in the HCV genome interfere with and disturb intracellular signal trans-
duction, often by phosphorylation of cellular proteins. Moreover, some of the
HCV-encoded proteins seem to serve as substrates for host cell protein kinases.
These phosphorylations affect the biological functions of the antigens. In many
cases it could be demonstrated that only short stretches of the linear sequence
of the viral or cellular proteins are involved and play a crucial role for these
phosphorylation events. The identiﬁcation of these small polypeptide elements and
the subsequent development of strategies to inhibit protein–protein interactions
involving them may be the ﬁrst step towards reducing the chronicity and/or of
the carcinogenicity of the virus. This review summarizes current knowledge of
intracellular phosphorylation processes that are affected by HCV.
Genome structure of HCV and polyprotein processing
HCV was identiﬁed as the causative agent of non-A, non-B Hepatitis in 1989
[19, 20]. Approximately 170 million people are infected with this virus worldwide.
At least 85% of the infected patients develop a chronic hepatitis. The major
complication of chronic HCV infection is cirrhosis of the liver, which occurs in 20