title: The resistance mutation R155K in the NS3/4A protease of hepatitis C virus also leads the virus to escape from HLA-A*68-restricted CD8 T cells.
abstract: The NS3/4A serine protease of the hepatitis C virus (HCV) is one of the most attractive targets for specific antiviral agents. However, mutations conferring resistance may decrease the efficacy of these drugs. Although the level of resistance associated with specific mutations differs between different compounds, substitutions R155K and A156T reduce susceptibility to all protease inhibitors published so far. Interestingly, variants harboring the resistant mutation R155K were also detected as the predominant quasispecies in some treatment-naïve patients. Of note, key positions for resistance overlap with the HLA-A*68-restricted epitope HAVGIFRAAV(1175-1184). The aim of our study was to analyze the impact of protease inhibitor resistance mutations on the replication level and the antiviral CD8 T cell response against this HCV epitope. Our findings suggest that the R155K variant is associated with a relatively high replication level and with a substantial loss of cross-recognition by specific CD8 T cells targeting the epitope HAVGIFRAAV(1175-1184), providing a possible explanation for its existence in the absence of drug selection pressure.
authors.affiliation: Institute for Virology, University of Duisburg-Essen, Virchowstrasse 179, 45147 Essen, Germany.
authors.forename: Shadi
authors.initials: S
authors.lastname: Salloum
authors.forename: Silvia F
authors.initials: SF
authors.lastname: Kluge
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.forename: Joerg
authors.initials: J
authors.lastname: Timm
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002219:Carbamates / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics*; D024882:Drug Resistance, Viral; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology*; D016174:Hepacivirus / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds / Q000494:pharmacology; D020125:Mutation, Missense; D011804:Quinolines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D011804:Quinolines; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C479555:BILN 2061; C053029:HLA-A*68 antigen; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus