title: Divergent adaptation of hepatitis C virus genotypes 1 and 3 to human leukocyte antigen-restricted immune pressure.
abstract: Many hepatitis C virus (HCV) infections worldwide are with the genotype 1 and 3 strains of the virus. Cellular immune responses are known to be important in the containment of HCV genotype 1 infection, and many genotype 1 T cell targets (epitopes) that are presented by host human leukocyte antigens (HLAs) have been identified. In contrast, there is almost no information known about the equivalent responses to genotype 3. Immune escape mechanisms used by HCV include the evolution of viral polymorphisms (adaptations) that abrogate this host-viral interaction. Evidence of HCV adaptation to HLA-restricted immune pressure on HCV can be observed at the population level as viral polymorphisms associated with specific HLA types. To evaluate the escape patterns of HCV genotypes 1 and 3, we assessed the associations between viral polymorphisms and specific HLA types from 187 individuals with genotype 1a and 136 individuals with genotype 3a infection. We identified 51 HLA-associated viral polymorphisms (32 for genotype 1a and 19 for genotype 3a). Of these putative viral adaptation sites, six fell within previously published epitopes. Only two HLA-associated viral polymorphisms were common to both genotypes. In the remaining sites with HLA-associated polymorphisms, there was either complete conservation or no significant HLA association with viral polymorphism in the alternative genotype. This study also highlights the diverse mechanisms by which viral evasion of immune responses may be achieved and the role of genotype variation in these processes.
  
  
  CONCLUSIONS
  There is little overlap in HLA-associated polymorphisms in the nonstructural proteins of HCV for the two genotypes, implying differences in the cellular immune pressures acting on these viruses and different escape profiles. These findings have implications for future therapeutic strategies to combat HCV infection, including vaccine design.
authors: University Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland.
authors: Andri
authors: A
authors: Rauch
authors: Ian
authors: I
authors: James
authors: Katja
authors: K
authors: Pfafferott
authors: David
authors: D
authors: Nolan
authors: Paul
authors: P
authors: Klenerman
authors: Wendy
authors: W
authors: Cheng
authors: Lindsay
authors: L
authors: Mollison
authors: Geoff
authors: G
authors: McCaughan
authors: Nick
authors: N
authors: Shackel
authors: Gary P
authors: GP
authors: Jeffrey
authors: Ross
authors: R
authors: Baker
authors: Elizabeth
authors: E
authors: Freitas
authors: Isla
authors: I
authors: Humphreys
authors: Hansjakob
authors: H
authors: Furrer
authors: Huldrych F
authors: HF
authors: Günthard
authors: Bernard
authors: B
authors: Hirschel
authors: Simon
authors: S
authors: Mallal
authors: Mina
authors: M
authors: John
authors: Michaela
authors: M
authors: Lucas
authors: Eleanor
authors: E
authors: Barnes
authors: Silvana
authors: S
authors: Gaudieri
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics* / Q000276:immunology*; D000328:Adult; D000483:Alleles; D001315:Australia; D015331:Cohort Studies; D004279:DNA, Viral / Q000235:genetics; D000939:Epitopes / Q000235:genetics; D005260:Female; D005838:Genotype; D006680:HLA Antigens / Q000276:immunology*; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D013557:Switzerland; D006113:United Kingdom
chemical_list: D004279:DNA, Viral; D000939:Epitopes; D006680:HLA Antigens; D012367:RNA, Viral