A complete mutational fitness map of the hepatitis C virus nonstructural 3 protease: relation to recognition by cytotoxic T lymphocytes.
The hepatitis C virus nonstructural (NS) 3/4A protease sequence is highly conserved for reasons not fully understood. We determined the protease activity in 181 NS3/4A gene products in which each protease residue was replaced by alanine or glycine. Unexpectedly, most (87%) protease residues could be replaced and protease activity would be retained. Using these data, we were able to identify a human leukocyte antigen A2-restricted epitope in which substitutions at 5 of 9 residues destroyed the protease. The NS3 protease shows an unexpectedly high plasticity, and it is therefore important to identify target sequences in which the appearance of mutations is restricted by viral fitness.
Soderholm
Jonas
J
Division of Clinical Virology, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86, Stockholm, Sweden.
Sallberg
Matti
M
D000086042:3C Viral Proteases; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005814:Genes, Viral / Q000235:genetics; D014644:Genetic Variation / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D016174:Hepacivirus / Q000201:enzymology / Q000235:genetics*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D013045:Species Specificity; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000086042:3C Viral Proteases; D003546:Cysteine Endopeptidases; D000939:Epitopes; D015789:HLA-A2 Antigen; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases