title: Escape from HLA-B*08-restricted CD8 T cells by hepatitis C virus is associated with fitness costs.
abstract: The inherent sequence diversity of the hepatitis C virus (HCV) represents a major hurdle for the adaptive immune system to control viral replication. Mutational escape within targeted CD8 epitopes during acute HCV infection has been well documented and is one possible mechanism for T-cell failure. HLA-B*08 was recently identified as one HLA class I allele associated with spontaneous clearance of HCV replication. Selection of escape mutations in the immunodominant HLA-B*08-restricted epitope HSKKKCDEL(1395-1403) was observed during acute infection. However, little is known about the impact of escape mutations in this epitope on viral replication capacity. Their previously reported reversion back toward the consensus residue in patients who do not possess the B*08 allele suggests that the consensus sequence in this epitope is advantageous for viral replication in the absence of immune pressure. The aim of this study was to determine the impact of mutational escape from this immunodominant epitope on viral replication. We analyzed it with a patient cohort with chronic HCV genotype 1b infection and in a single-source outbreak (genotype 1b). Sequence changes in this highly conserved region are rare and selected almost exclusively in the presence of the HLA-B*08 allele. When tested in the subgenomic replicon (Con1), the observed mutations reduce viral replication compared with the prototype sequence. The results provide direct evidence that escape mutations in this epitope are associated with fitness costs and that the antiviral effect of HLA-B*08-restricted T cells is sufficiently strong to force the virus to adopt a relatively unfavorable sequence.
authors.affiliation: University of Essen, Department of Virology, Virchowstrasse 179, 45147 Essen, Germany.
authors.forename: Shadi
authors.initials: S
authors.lastname: Salloum
authors.forename: Cesar
authors.initials: C
authors.lastname: Oniangue-Ndza
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: Laura
authors.initials: L
authors.lastname: Hudson
authors.forename: Silvia
authors.initials: S
authors.lastname: Giugliano
authors.forename: Marc
authors.initials: M
authors.lastname: aus dem Siepen
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
authors.forename: Manfred
authors.initials: M
authors.lastname: Wiese
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Helen
authors.initials: H
authors.lastname: Bright
authors.forename: Norbert
authors.initials: N
authors.lastname: Scherbaum
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.forename: Sergei
authors.initials: S
authors.lastname: Viazov
authors.forename: Joerg
authors.initials: J
authors.lastname: Timm
mesh_terms: D000483:Alleles; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics / Q000502:physiology*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006801:Humans; D016056:Immunodominant Epitopes; D009154:Mutation; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D016056:Immunodominant Epitopes; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases