title: Naturally occurring resistance mutations within the core and NS5B regions in hepatitis C genotypes, particularly genotype 5a, in South Africa.
abstract: Approximately 1 million South Africans are infected with Hepatitis C virus (HCV). The standard of care (SOC) in South Africa is combination therapy (pegylated interferon and ribavirin). HCV genotypes and/or mutations in the core/non-structural regions have been associated with response to therapy and/or disease progression. This study examines mutations in the core (29-280 amino acids, including ∼ 90 E1 amino acids) and NS5B (241-306 amino acids) regions on pre-treatment isolates from patients attending Johannesburg hospitals or asymptomatic South African blood donors. Diversity within known CD4+ and CD8+ T-cell epitopes was also explored. Samples grouped into subtypes 1a(N = 10) 1b(N = 12), 3a(N = 5), 4a(N = 3) and 5a(N = 61). Two mutations, associated with interferon resistance-R70Q and T110N-were present in 29 genotype 5a core sequences. No resistance mutation to NS5B nucleotide inhibitors, sofosbuvir was found. Six putative CD8+ and one CD4+ T-cell epitope sequence in the core region showed binding scores of <300 IC50nM to HLA alleles frequently observed in the South African population. No known CD8+ and CD4+ T-cell epitopes were mapped in the NS5B region. The analysis begs the question whether those infected with genotype 5a will benefit better on interferon-free combination therapies. This study provides new insight into one of the lesser studied HCV genotypes and compares the diversity seen in a large pre-treatment cohort with other subtypes.
authors.affiliation: Centre for Vaccines and Immunology, National Institute for Communicable Diseases (NICD), Sandringham, Johannesburg, South Africa; Faculty of Health Sciences, School of Pathology, Division of Virology and Communicable Diseases Surveillance, University of Witwatersrand, Johannesburg, South Africa. Electronic address: niship@nicd.ac.za.
authors.forename: N
authors.initials: N
authors.lastname: Prabdial-Sing
authors.affiliation: Department of Internal Medicine Division of Digestive Diseases, University of Cincinnati Medical Centre, Cincinnati, OH, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Blackard
authors.affiliation: Faculty of Health Sciences, School of Pathology, Division of Virology and Communicable Diseases Surveillance, University of Witwatersrand, Johannesburg, South Africa; Centre for HIV/STI, National Institute for Communicable Diseases (NICD), Sandringham, Johannesburg, South Africa.
authors.forename: A J
authors.initials: AJ
authors.lastname: Puren
authors.affiliation: Gastroenterology Department, University of the Witwatersrand and Charlotte Maxeke Hospital, Johannesburg, South Africa.
authors.forename: A
authors.initials: A
authors.lastname: Mahomed
authors.affiliation: Gastroenterology Department, University of the Witwatersrand and Chris Hani Baragwanath Hospital, Johannesburg, South Africa.
authors.forename: W
authors.initials: W
authors.lastname: Abuelhassan
authors.affiliation: Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Hospital, Johannesburg, and National Health Laboratory Services (NHLS), South Africa.
authors.forename: J
authors.initials: J
authors.lastname: Mahlangu
authors.affiliation: Donation Testing, South African National Blood Service, Roodepoort, South Africa.
authors.forename: M
authors.initials: M
authors.lastname: Vermeulen
authors.affiliation: Department of Medical Virology, University of Pretoria, Pretoria, South Africa; Tshwane Academic Division, NHLS, Pretoria, South Africa.
authors.forename: S M
authors.initials: SM
authors.lastname: Bowyer
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006680:HLA Antigens / Q000276:immunology; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D012367:RNA, Viral / Q000235:genetics; D012254:Ribavirin / Q000627:therapeutic use; D020539:Sequence Analysis, Protein; D013019:South Africa; D014758:Viral Core Proteins / Q000235:genetics*; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D007372:Interferons; D012367:RNA, Viral; D012254:Ribavirin; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Genotype 5; Hepatitis C; Interferon; Mutations; Therapy