Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection.
Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations. Associations between polymorphisms within NS3 and HLA class I alleles were assessed in 118 individuals from Western Australia and Switzerland with chronic hepatitis C infection, of whom 82 (69%) were coinfected with human immunodeficiency virus. The levels and locations of amino acid polymorphisms exhibited within NS3 were remarkably similar between the two cohorts and revealed regions under functional constraint and selective pressures. We identified specific HCV mutations within and flanking published epitopes with the correct HLA restriction and predicted escaped amino acid. Additional HLA-restricted mutations were identified that mark putative epitopes targeted by cell-mediated immune responses. This analysis of host-virus interaction reveals evidence of HCV adaptation to HLA class I-restricted immune pressure and identifies in vivo targets of cellular immune responses at the population level.
Gaudieri
Silvana
S
Centre for Clinical Immunology and Biomedical Statistics, Level 2, North Block, Royal Perth Hospital, Wellington St., Perth, Western Australia 6000, Australia.
Rauch
Andri
A
Park
Lawrence P
LP
Freitas
Elizabeth
E
Herrmann
Susan
S
Jeffrey
Gary
G
Cheng
Wendy
W
Pfafferott
Katja
K
Naidoo
Kiloshni
K
Chapman
Russell
R
Battegay
Manuel
M
Weber
Rainer
R
Telenti
Amalio
A
Furrer
Hansjakob
H
James
Ian
I
Lucas
Michaela
M
Mallal
Simon A
SA
D000220:Adaptation, Biological; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D000939:Epitopes / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005805:Genes, MHC Class I; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D013223:Statistics as Topic; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases