High amino acid variability within the NS5A of hepatitis C virus (HCV) is associated with hepatocellular carcinoma in patients with HCV-1b-related cirrhosis

Interferon therapy may decrease the risk of hepatocellular carcinoma in pat ients with hepatitis C virus (HCV)-related liver cirrhosis. Interaction of the cellular protein kinase PKR with the PKR-binding domain (PKR-bd) of HCV -NS5A protein may affect cellular growth control and viral resistance to in terferon therapy. Mutations within the PKR-bd, which comprises the interfer on sensitivity determining region (ISDR), have been associated with interfe ron sensitivity. To determine whether or not there is an association betwee n HCV heterogeneity and the presence of hepatocellular carcinoma, HCV-lb ge nomic regions were amplified and directly sequenced from serum samples obta ined from 82 patients with liver cirrhosis, 53 with, and 29 without hepatoc ellular carcinoma. None of them had received anti-viral therapy. When compa red with the deduced consensus sequence, the median number of amino acid ch anges in the PKR-bd was higher among samples from patients with (4.22) than from those without hepatocellular carcinoma (1.62; P < .001), and isolates with 3 or more amino acid changes were significantly more common among the former (60%) than among the later (6%, P < .001). No such differences were observed in other viral regions, including Core, E2-HVR-1, E2-PePHD, NS3, and the 5 ' and 3 ' PKR-bd flanking regions. In addition, amino acid variat ion in viral regions other than HVR-1 did not accumulate over time in the a nalyzed sequential serum samples obtained from patients with or without hep atocellular carcinoma. Therefore, a mutated HCV-PKR-bd phenotype is very co mmon in cirrhotic patients with hepatocellular carcinoma.