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 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.
Giménez-Barcons
M
M
Liver Unit, Institut de Malalties Digestives, Departament de Medicina, IDIBAPS, Hospital Clínic, University of Barcelona, Spain.
Franco
S
S
Suárez
Y
Y
Forns
X
X
Ampurdanès
S
S
Puig-Basagoiti
F
F
Sánchez-Fueyo
A
A
Barrera
J M
JM
Llovet
J M
JM
Bruix
J
J
Sánchez-Tapias
J M
JM
Rodés
J
J
Saiz
J C
JC
D000368:Aged; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D004352:Drug Resistance, Microbial; D005260:Female; D016174:Hepacivirus / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000821:virology*; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D016415:Sequence Alignment; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics; D019892:eIF-2 Kinase / Q000737:chemistry / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D007372:Interferons; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; D019892:eIF-2 Kinase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase