title: Compensatory mutations restore the replication defects caused by cytotoxic T lymphocyte escape mutations in hepatitis C virus polymerase.
abstract: While human leukocyte antigen B57 (HLA-B57) is associated with the spontaneous clearance of hepatitis C virus (HCV), the mechanisms behind this control remain unclear. Immunodominant CD8(+) T cell responses against the B57-restricted epitopes comprised of residues 2629 to 2637 of nonstructural protein 5B (NS5B(2629-2637)) (KSKKTPMGF) and E2(541-549) (NTRPPLGNW) were recently shown to be crucial in the control of HCV infection. Here, we investigated whether the selection of deleterious cytotoxic T lymphocyte (CTL) escape mutations in the NS5B KSKKTPMGF epitope might impair viral replication and contribute to the B57-mediated control of HCV. Common CTL escape mutations in this epitope were identified from a cohort of 374 HCV genotype 1a-infected subjects, and their impact on HCV replication assessed using a transient HCV replicon system. We demonstrate that while escape mutations at residue 2633 (position 5) of the epitope had little or no impact on HCV replication in vitro, mutations at residue 2629 (position 1) substantially impaired replication. Notably, the deleterious mutations at position 2629 were tightly linked in vivo to upstream mutations at residue 2626, which functioned to restore the replicative defects imparted by the deleterious escape mutations. These data suggest that the selection of costly escape mutations within the immunodominant NS5B KSKKTPMGF epitope may contribute in part to the control of HCV replication in B57-positive individuals and that persistence of HCV in B57-positive individuals may involve the development of specific secondary compensatory mutations. These findings are reminiscent of the selection of deleterious CTL escape and compensatory mutations by HLA-B57 in HIV-1 infection and, thus, may suggest a common mechanism by which alleles like HLA-B57 mediate protection against these highly variable pathogens.
authors: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
authors: Cesar
authors: C
authors: Oniangue-Ndza
authors: Thomas
authors: T
authors: Kuntzen
authors: Michael
authors: M
authors: Kemper
authors: Andrew
authors: A
authors: Berical
authors: Yaoyu E
authors: YE
authors: Wang
authors: Christoph
authors: C
authors: Neumann-Haefelin
authors: Peter Kristian
authors: PK
authors: Foote
authors: Kelsey
authors: K
authors: Hills-Evans
authors: Laura L
authors: LL
authors: Reyor
authors: Katherine
authors: K
authors: Kane
authors: Adrianne D
authors: AD
authors: Gladden
authors: Allyson K
authors: AK
authors: Bloom
authors: Karen A
authors: KA
authors: Power
authors: Robert
authors: R
authors: Thimme
authors: Georg M
authors: GM
authors: Lauer
authors: Matthew R
authors: MR
authors: Henn
authors: Arthur Y
authors: AY
authors: Kim
authors: Todd M
authors: TM
authors: Allen
mesh_terms: D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006801:Humans; D020125:Mutation, Missense; D013489:Suppression, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
chemical_list: D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D017361:Viral Nonstructural Proteins; C103707:HLA-B57 antigen; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase