title: Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy.
abstract: The efficacy of specifically targeted anti-viral therapy for hepatitis C virus (HCV) (STAT-C), including HCV protease and polymerase inhibitors, is limited by the presence of drug-specific viral resistance mutations within the targeted proteins. Genetic diversity within these viral proteins also evolves under selective pressures provided by host human leukocyte antigen (HLA)-restricted immune responses, which may therefore influence STAT-C treatment response. Here, the prevalence of drug resistance mutations relevant to 27 developmental STAT-C drugs, and the potential for drug and immune selective pressures to intersect at sites along the HCV genome, is explored. HCV nonstructural (NS) 3 protease or NS5B polymerase sequences and HLA assignment were obtained from study populations from Australia, Switzerland, and the United Kingdom. Four hundred five treatment-naïve individuals with chronic HCV infection were considered (259 genotype 1, 146 genotype 3), of which 38.5% were coinfected with human immunodeficiency virus (HIV). We identified preexisting STAT-C drug resistance mutations in sequences from this large cohort. The frequency of the variations varied according to individual STAT-C drug and HCV genotype/subtype. Of individuals infected with subtype 1a, 21.5% exhibited genetic variation at a known drug resistance site. Furthermore, we identified areas in HCV protease and polymerase that are under both potential HLA-driven pressure and therapy selection and identified six HLA-associated polymorphisms (P <or= 0.05) at known drug resistance sites.
  
  
  CONCLUSIONS
  Drug and host immune responses are likely to provide powerful selection forces that shape HCV genetic diversity and replication dynamics. Consideration of HCV viral adaptation in terms of drug resistance as well as host "immune resistance" in the STAT-C treatment era could provide important information toward an optimized and individualized therapy for chronic hepatitis C.
authors.affiliation: Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Western Australia, Australia.
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.forename: Andri
authors.initials: A
authors.lastname: Rauch
authors.forename: Katja
authors.initials: K
authors.lastname: Pfafferott
authors.forename: Eleanor
authors.initials: E
authors.lastname: Barnes
authors.forename: Wendy
authors.initials: W
authors.lastname: Cheng
authors.forename: Geoff
authors.initials: G
authors.lastname: McCaughan
authors.forename: Nick
authors.initials: N
authors.lastname: Shackel
authors.forename: Gary P
authors.initials: GP
authors.lastname: Jeffrey
authors.forename: Lindsay
authors.initials: L
authors.lastname: Mollison
authors.forename: Ross
authors.initials: R
authors.lastname: Baker
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Freitas
authors.forename: Isla
authors.initials: I
authors.lastname: Humphreys
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Stuart
authors.initials: S
authors.lastname: Roberts
authors.forename: David
authors.initials: D
authors.lastname: Nolan
authors.forename: Michaela
authors.initials: M
authors.lastname: Lucas
mesh_terms: D000220:Adaptation, Biological; D000596:Amino Acids / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral / Q000235:genetics*; D014644:Genetic Variation; D016679:Genome, Viral; D005838:Genotype; D015658:HIV Infections / Q000150:complications; D006680:HLA Antigens / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D006801:Humans; D008969:Molecular Sequence Data; D012641:Selection, Genetic; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000596:Amino Acids; D000998:Antiviral Agents; D006680:HLA Antigens; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase