title: Hepatitis C virus infection causes cell cycle arrest at the level of initiation of mitosis.
abstract: Chronic infection with the hepatitis C virus (HCV) is associated with increased risk for hepatocellular carcinoma (HCC). Chronic immune-mediated inflammation is likely to be an important factor in the development of HCV-associated HCC, but direct effects of HCV infection on the host cell cycle may also play a role. Although overexpression studies have revealed multiple interactions between HCV-encoded proteins and host cell cycle regulators and tumor suppressor proteins, the relevance of these observations to HCV-associated liver disease is not clear. We determined the net effect of these interactions on regulation of the cell cycle in the context of virus infection. Flow cytometry of HCV-infected carboxyfluorescein succinimidyl ester-labeled hepatoma cells indicated a slowdown in proliferation that correlated with abundance of viral antigen. A decrease in the proportions of infected cells in G(1) and S phases with an accumulation of cells in G(2)/M phase was observed, compared to mock-infected controls. Dramatic decreases in markers of mitosis, such as phospho-histone H3, in infected cells suggested a block to mitotic entry. In common with findings described in the published literature, we observed caspase 3 activation, suggesting that cell cycle arrest is associated with apoptosis. Differences were observed in patterns of cell cycle disturbance and levels of apoptosis with different strains of HCV. However, the data suggest that cell cycle arrest at the interface of G(2) and mitosis is a common feature of HCV infection.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Center for Translational Research, Inﬂammatory Diseases Institute, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA. mcgivern@med.unc.edu
authors.forename: Rathi P
authors.initials: RP
authors.lastname: Kannan
authors.forename: Lucinda L
authors.initials: LL
authors.lastname: Hensley
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Evers
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
authors.forename: David R
authors.initials: DR
authors.lastname: McGivern
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry; D005452:Fluoresceins; D005455:Fluorescent Antibody Technique; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology*; D006657:Histones / Q000096:biosynthesis; D006801:Humans; D008938:Mitosis; D013388:Succinimides
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D006657:Histones; D013388:Succinimides; D053148:Caspase 3