title: Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution.
abstract: CD8(+) T cell responses play a key role in governing the outcome of hepatitis C virus (HCV) infection, and viral evolution enabling escape from these responses may contribute to the inability to resolve infection. To more comprehensively examine the extent of CD8 escape and adaptation of HCV to human leukocyte antigen (HLA) class I restricted immune pressures on a population level, we sequenced all non-structural proteins in a cohort of 70 chronic HCV genotype 1a-infected subjects (28 subjects with HCV monoinfection and 42 with HCV/human immunodeficiency virus [HIV] coinfection). Linking of sequence polymorphisms with HLA allele expression revealed numerous HLA-associated polymorphisms across the HCV proteome. Multiple associations resided within relatively conserved regions, highlighting attractive targets for vaccination. Additional mutations provided evidence of HLA-driven fixation of sequence polymorphisms, suggesting potential loss of some CD8 targets from the population. In a subgroup analysis of mono- and co-infected subjects some associations lost significance partly due to reduced power of the utilized statistics. A phylogenetic analysis of the data revealed the substantial influence of founder effects upon viral evolution and HLA associations, cautioning against simple statistical approaches to examine the influence of host genetics upon sequence evolution of highly variable pathogens.
  
  
  CONCLUSIONS
  These data provide insight into the frequency and reproducibility of viral escape from CD8(+) T cell responses in human HCV infection, and clarify the combined influence of multiple forces shaping the sequence diversity of HCV and other highly variable pathogens.
authors.affiliation: Partners AIDS Research Center, Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Joerg
authors.initials: J
authors.lastname: Timm
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Marcus G
authors.initials: MG
authors.lastname: Daniels
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.forename: Laura L
authors.initials: LL
authors.lastname: Reyor
authors.forename: Rachel
authors.initials: R
authors.lastname: Allgaier
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuntzen
authors.forename: Will
authors.initials: W
authors.lastname: Fischer
authors.forename: Brian E
authors.initials: BE
authors.lastname: Nolan
authors.forename: Jared
authors.initials: J
authors.lastname: Duncan
authors.forename: Julian
authors.initials: J
authors.lastname: Schulze zur Wiesch
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Kim
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
authors.forename: Bette T
authors.initials: BT
authors.lastname: Korber
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
mesh_terms: D000595:Amino Acid Sequence; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D005805:Genes, MHC Class I; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D010802:Phylogeny; D016415:Sequence Alignment; D017361:Viral Nonstructural Proteins / Q000737:chemistry*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D017361:Viral Nonstructural Proteins