Hepatitis C virus encodes a selenium-dependent glutathione peroxidase gene. Implications for oxidative stress as a risk factor in progression to hepatocellular carcinoma.
OBJECTIVE
Using structural bioinformatics methods, the aim is to assess the hypothesis that hepatitis C virus (HCV) encodes a glutathione peroxidase (GPx) gene in an overlapping reading frame, linking HCV expression and pathogenesis to the Se status and dietary oxidant/Antioxidant balance of the host.


METHODS
The putative HCV GPx gene was identified by searching viral sequence databases, using conserved GPx active site sequences as probes, giving particular weight to the UGA (selenocysteine) codon. Multiple sequence alignments were generated and analyzed to validate the sequence similarity, and to establish the degree of conservation of the identified genomic features in HCV. Molecular modeling was used to assess the structural feasibility of the proposed homology.


RESULTS
The GPx homology region overlaps the NS4 gene, and is well conserved in HCV. The sequence similarity of the conserved active site regions to a set of known GPx is high (4 to 6 SD greater than expected for similar random sequences). The computed strain energy of a molecular model of the HCV GPx is energetically favorable, comparable to the bovine GPx structure.


CONCLUSIONS
By linking HCV replication and pathogenesis to the Se status and dietary oxidant/antioxidant balance of the host, the existence of a viral GPx gene could help to explain why HCV disease progression is accelerated by oxidant stresses such as alcoholism and iron overload.
Zhang
W
W
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, USA.
Cox
A G
AG
Taylor
E W
EW
D000595:Amino Acid Sequence / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018450:Disease Progression; D005979:Glutathione Peroxidase / Q000235:genetics*; D016174:Hepacivirus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D008957:Models, Genetic; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000235:genetics*; D016364:Reading Frames; D012307:Risk Factors; D012643:Selenium / Q000097:blood; D017279:Selenocysteine / Q000235:genetics
D017279:Selenocysteine; D005979:Glutathione Peroxidase; D012643:Selenium