Journal
GASTROENTEROLOGY
Volume 140, Issue 2, Pages 686-U434Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2010.09.042
Keywords
CD8 T Cell; HLA-B57; Spontaneous Clearance; Viral Escape
Categories
Funding
- National Institutes of Health [AI 054379, AI 066345, AI 031563, AI 042851, AI 067926, AI 069939, DK 078772, AI 062435]
- Harvard Medical School Center for AIDS Research [P30 AI060354]
- Campbell Foundation
- Liver Foundation
- Doris Duke Charitable Foundation
- Howard Hughes Medical Institute
- Deutsche Forschungsgemeinschaft [DFG KU2250/1-1]
Ask authors/readers for more resources
BACKGROUND & AIMS: HLA class I alleles are linked to spontaneous control of hepatitis C virus (HCV) and human immunodeficiency virus-1, but for HCV the roles of particular alleles and corresponding CD8(+) T-cell responses remain incompletely defined. We aimed to determine the correlations between these alleles and natural outcomes of HCV and determine associated key T-cell responses. METHODS: In a cohort of HCV individuals, we determined HLA class I alleles, HCV outcomes, T-cell responses, and examined sequence data for mutational changes within key epitopes. RESULTS: Carriage of HLA-B*57 was associated with a higher rate of viral clearance (risk ratio = 2.0; 95% confidence interval: 1.2-3.4), while HLA-B*08 was associated with a lower rate (risk ratio = 0.34; 95% confidence interval: 0.1-0.9]. Two HLA-B*57-restricted T-cell epitopes were targeted in spontaneous clearance; subjects with chronic viremia expressing HLA-B*57 harbored HCV strains with a high frequency of mutations in key residues. HLAB*57-mediated escape was supported by diminished immune recognition of these variants and acute HCV infection revealing viral evolution toward less recognized variants. Analysis of a genotype 1b strain from a single-source HCV outbreak in which HLA-B*57 was not protective revealed sequence variations that interfere with immunogenicity, thereby preventing HLA-B*57-mediated immune pressure. CONCLUSIONS: Our data indicate a role of HLA-B*57-restricted CD8(+) T-cell responses in mediating spontaneous clearance and evolution in HCV infection, and viral strains containing epitope variants that are less recognized abrogate the protective effects of HLA-B*57. The finding that HLAB*57-mediated antiviral immunity is associated with control of both human immunodeficiency virus-1 and HCV suggests a common shared mechanism of a successful immune response against persistent viruses.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available