Hepatology 2001 Jul;34(1):158-67
High amino acid variability within the NS5A of hepatitis C virus (HCV) is associated with hepatocellular carcinoma in patients with HCV-1b-related cirrhosis.
Gimenez-Barcons M, Franco S, Suarez Y, Forns X, Ampurdanes S, Puig-Basagoiti F, Sanchez-Fueyo A, Barrera JM, Llovet JM, Bruix J, Sanchez-Tapias JM, Rodes J, Saiz JC.
Liver Unit, Institut de Malalties Digestives, Departament de Medicina, IDIBAPS, Hospital Clinic, University of Barcelona, Spain.
Interferon therapy may decrease
the risk of hepatocellular carcinoma in patients 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 interferon therapy. Mutations within the PKR-bd, which comprises
the interferon sensitivity determining region (ISDR), have been associated with
interferon sensitivity. To determine whether or not there is an association
between HCV heterogeneity and the presence of hepatocellular carcinoma, HCV-1b
genomic regions were amplified and directly sequenced from serum samples obtained
from 82 patients with liver cirrhosis, 53 with, and 29 without hepatocellular
carcinoma. None of them had received antiviral therapy. When compared with the
deduced consensus sequence, the median number of amino acid changes 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 variation in viral regions other than HVR-1 did not accumulate
over time in the analyzed sequential serum samples obtained from patients with
or without hepatocellular carcinoma. Therefore, a mutated HCV-PKR-bd phenotype
is very common in cirrhotic patients with hepatocellular carcinoma