title: Evaluating the Role of Cellular Immune Responses in the Emergence of HCV NS3 Resistance Mutations During Protease Inhibitor Therapy.
abstract: The efficacy of protease inhibitor drugs in hepatitis C virus (HCV) treatment is limited by the selection and expansion of drug-resistant mutations. HCV replication is error-prone and genetic variability within the dominant epitopes ensures its persistence. The aims of this study are to evaluate the role of cellular immune response in the emergence of HCV protease resistance mutations and its effects on treatment outcome. Ten chronically HCV-infected subjects were treated with boceprevir (BOC)-based triple therapy. HCV-RNA was tested for BOC resistance-associated viral variants. HCV protease resistance mutations were investigated pretreatment and 24 weeks post-treatment. Synthetic peptides representing the wild-type and the potential nonstructural (NS)3 variants were used to evaluate T cell responses and human leukocyte antigen binding. Sustained viral response was achieved in 70% of patients, two patients were treatment nonresponders (NRs) and one was classified as a relapse. Pretreatment, the proportion of drug-resistant variants within individuals was higher in sustained viral responders (SVRs) than in NR patients. However, resistance-associated variants increased in NRs after BOC combined triple therapy. In contrast to NR patients, significant stronger cell-mediated immune responses were observed at the baseline among those who achieved sustained viral response for all T cell epitopes tested. Despite the increase in cell-mediated immune responses at week 24 in NRs, they failed to control the virus replication, leading to development of overt drug-resistant variants. Our data suggest that strong NS3-specific T cell immune responses at the baseline may predict a positive outcome of directly acting antiviral-based therapy, and the presence of pre-existent resistance mutations does not play a significant role in the outcome of anti-HCV combined therapy.
authors.affiliation: 1 Department of Internal Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Enass A
authors.initials: EA
authors.lastname: Abdel-Hameed
authors.affiliation: 1 Department of Internal Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Rouster
authors.affiliation: 2 Division of Asthma Research, Pyrosequencing Core for Genetic and Epigenetic Studies, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.affiliation: 2 Division of Asthma Research, Pyrosequencing Core for Genetic and Epigenetic Studies, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio.
authors.forename: Ashley
authors.initials: A
authors.lastname: Ulm
authors.affiliation: 3 Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University , Assiut, Egypt .
authors.forename: Helal F
authors.initials: HF
authors.lastname: Hetta
authors.affiliation: 1 Department of Internal Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Anwar
authors.affiliation: 1 Department of Internal Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Sherman
authors.affiliation: 1 Department of Internal Medicine, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Mohamed Tarek M
authors.initials: MT
authors.lastname: Shata
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D006680:HLA Antigens / Q000276:immunology; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010865:Pilot Projects; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D006680:HLA Antigens; D011392:Proline; D011480:Protease Inhibitors; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide