title: Limited effect on NS3-NS4A protein cleavage after alanine substitutions within the immunodominant HLA-A2-restricted epitope of the hepatitis C virus genotype 3a non-structural 3/4A protease.
abstract: It has been well established that immunological escape mutations within the hepatitis C virus genotype (gt) 1a non-structural (NS) 3/4A protease are partly prevented by a reduction in viral protease fitness. Surprisingly little is known about whether similar mutations affect proteases from other genotypes. In the present study, we assessed both the HLA-A2-restricted CTL response and gt3a NS3/4A protease fitness. Similar to gt1, the 1073-1081 epitope was immunodominant within the gt3a-specific HLA-A2-restricted CTL response, despite sequence similarity of only 56 % between the gt1a and gt3a genes. However, unlike the gt1a NS3/4A protease, all residues within the gt3a 1073-1081 epitope could be replaced sequentially by alanine while retaining protease activity, at least in part.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Gustaf
authors.initials: G
authors.lastname: Ahlén
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Antony
authors.initials: A
authors.lastname: Chen
authors.affiliation: Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Roe
authors.affiliation: Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, S-581 83 Linköping, Sweden.
authors.forename: Tina
authors.initials: T
authors.lastname: Falkeborn
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Frelin
authors.affiliation: Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: William W
authors.initials: WW
authors.lastname: Hall
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Sällberg
authors.affiliation: Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, S-413 46 Gothenburg, Sweden.|Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Söderholm
mesh_terms: D000409:Alanine / Q000737:chemistry*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D003001:Cloning, Molecular; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics*; D008969:Molecular Sequence Data; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000409:Alanine; D016056:Immunodominant Epitopes; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080107:NS4B protein, flavivirus