title: Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue.
abstract: Analysis of hepatitis C virus (HCV) replication and quasispecies distribution within the tumor of patients with HCV-associated hepatocellular carcinoma (HCC) can provide insight into the role of HCV in hepatocarcinogenesis and, conversely, the effect of HCC on the HCV lifecycle. In a comprehensive study of serum and multiple liver specimens from patients with HCC who underwent liver transplantation, we found a sharp and significant decrease in HCV RNA in the tumor compared with surrounding nontumorous tissues, but found no differences in multiple areas of control non-HCC cirrhotic livers. Diminished HCV replication was not associated with changes in miR-122 expression. HCV genetic diversity was significantly higher in livers containing HCC compared with control non-HCC cirrhotic livers. Tracking of individual variants demonstrated changes in the viral population between tumorous and nontumorous areas, the extent of which correlated with the decline in HCV RNA, suggesting HCV compartmentalization within the tumor. In contrast, compartmentalization was not observed between nontumorous areas and serum, or in controls between different areas of the cirrhotic liver or between liver and serum. Our findings indicate that HCV replication within the tumor is restricted and compartmentalized, suggesting segregation of specific viral variants in malignant hepatocytes.
authors.affiliation: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Djamila
authors.initials: D
authors.lastname: Harouaka
authors.affiliation: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Engle
authors.affiliation: Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Kurt
authors.initials: K
authors.lastname: Wollenberg
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, 09100 Cagliari, Italy;
authors.forename: Giacomo
authors.initials: G
authors.lastname: Diaz
authors.affiliation: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Tice
authors.affiliation: Liver Transplantation Center, Brotzu Hospital, 09100 Cagliari, Italy;
authors.forename: Fausto
authors.initials: F
authors.lastname: Zamboni
authors.affiliation: Department of Pathology, Rancho Los Amigos, University of Southern California, Los Angeles, CA 90242;
authors.forename: Sugantha
authors.initials: S
authors.lastname: Govindarajan
authors.affiliation: Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892; halter@dtm.cc.nih.gov pfarci@niaid.nih.gov.
authors.forename: Harvey
authors.initials: H
authors.lastname: Alter
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; halter@dtm.cc.nih.gov pfarci@niaid.nih.gov.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Farci
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000821:virology*; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000821:virology*; D012367:RNA, Viral / Q000235:genetics; D014779:Virus Replication
chemical_list: D012367:RNA, Viral
keywords: HCV RNA levels; HCV quasispecies; hepatitis C virus; hepatocellular carcinoma; liver