title: Association between variants in the interferon lambda 4 locus and substitutions in the hepatitis C virus non-structural protein 5A.
abstract: OBJECTIVE
  Single nucleotide polymorphisms within the interferon lambda 4 (IFNL4) locus are strongly associated with spontaneous clearance of hepatitis C virus (HCV) infection and early viral response to interferon therapy. Interaction between host genotype and amino acid substitutions might also influence the risk of antiviral resistance in interferon-free direct acting antiviral (DAA) therapies.
  
  
  METHODS
  The relationship between IFNL4 genotype and HCV substitutions was analyzed in 929 patients with chronic HCV genotype 1b infection. Ultra-deep sequencing and quasispecies reconstruction was performed on the N-terminal region of NS5A in 57 patients.
  
  
  RESULTS
  IFNL4 genotype was strongly associated with HCV NS5A Y93 and core protein substitutions, and the number and diversity of predicted quasispecies was marginally greater in IFNL4 TT/TT patients compared to TT/ΔG, ΔG/ΔG patients. RNA secondary structure prediction of the NS5A region suggests that variable sites are more likely to occupy unpaired, high entropy positions.
  
  
  CONCLUSIONS
  HCV infection is proposed to induce a more efficient antiviral response in individuals with the IFNL4 TT/TT genotype that results either in viral clearance or selection for viral adaptations. The association between IFNL4 TT/TT genotype and Y93 substitutions may impact the risk of antiviral resistance in NS5A inhibitors in DAA therapy.
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors: Sakura
authors: S
authors: Akamatsu
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: C Nelson
authors: CN
authors: Hayes
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: Hidenori
authors: H
authors: Ochi
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors: Takuro
authors: T
authors: Uchida
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors: Hiromi
authors: H
authors: Kan
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors: Eisuke
authors: E
authors: Murakami
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: Hiromi
authors: H
authors: Abe
authors: Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.
authors: Masataka
authors: M
authors: Tsuge
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: Daiki
authors: D
authors: Miki
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: Rie
authors: R
authors: Akiyama
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: Nobuhiko
authors: N
authors: Hiraga
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: Michio
authors: M
authors: Imamura
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
authors: Hiroshi
authors: H
authors: Aikata
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: Tomokazu
authors: T
authors: Kawaoka
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: Yoshiiku
authors: Y
authors: Kawakami
authors: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan. Electronic address: chayama@hiroshima-u.ac.jp.
authors: Kazuaki
authors: K
authors: Chayama
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral; D005260:Female; D056426:Genetic Loci; D005838:Genotype; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D000095022:Interferon Lambda; D012324:RNA-Dependent RNA Polymerase
chemical_list: D007378:Interleukins; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C579163:IFNL4 protein, human; D000095022:Interferon Lambda; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Antiviral resistance; Daclatasvir; Direct acting antivirals; HCV core protein; ISDR; Interferon lambda 4; NS5A; Next generation sequencing; Positive selection; Quasispecies