Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue

Significance

Hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection is the fastest-rising cause of cancer-related death in the United States. The level of intratumor HCV replication and the molecular interactions between virus and tumor remain elusive, however. Here we demonstrate that the ability of HCV to replicate in HCC is severely hampered despite unchanged miR122 expression. Surprisingly, we found that livers containing HCC harbor a more diverse viral population than that seen in cirrhotic livers without HCC. Tracking of individual variants demonstrated changes in quasispecies distribution between tumor and nontumorous areas, suggesting viral compartmentalization within the tumor. These insights into the interplay between HCV and HCC call for further investigation of whether malignant hepatocytes express or lack factors that restrict HCV entry or negatively affect viral replication.

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.