Compensatory mutations restore the replication defects caused by cytotoxic T lymphocyte escape mutations in hepatitis C virus polymerase.

J Virol
Authors
Keywords
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.

Year of Publication
2011
Journal
J Virol
Volume
85
Issue
22
Pages
11883-90
Date Published
2011 Nov
ISSN
1098-5514
URL
DOI
10.1128/JVI.00779-11
PubMed ID
21880756
PubMed Central ID
PMC3209273
Links
Grant list
T32 AI007387 / AI / NIAID NIH HHS / United States
U19-AI066345 / AI / NIAID NIH HHS / United States
U19-AI082630 / AI / NIAID NIH HHS / United States
R01 AI067926 / AI / NIAID NIH HHS / United States
U19 AI082630 / AI / NIAID NIH HHS / United States
U19 AI066345 / AI / NIAID NIH HHS / United States
R01-AI067926 / AI / NIAID NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States