Faculty Collaboration Database

Analysis of the evolutionary forces in an immunodominant CD8 epitope in hepatitis C virus at a population level. J Virol 2008 Apr;82(7):3438-51

Date

01/25/2008

Pubmed ID

18216107

Pubmed Central ID

PMC2268453

DOI

10.1128/JVI.01700-07

Scopus ID

2-s2.0-41149132755 (requires institutional sign-in at Scopus site)   56 Citations

Abstract

Failure of the adaptive immune response to control infection with the hepatitis C virus (HCV) can result from mutational escape in targeted T-cell epitopes. Recent studies suggest that T-cell immune pressure is an important factor in the evolution of the nonstructural proteins in HCV. The aim of this study was to characterize the forces that contribute to viral evolution in an HLA-A*01-restricted epitope in HCV NS3. This epitope represents a potentially attractive target for vaccination strategies since it is conserved across all genotypes. In our cohort of subjects with chronic HCV infection (genotype 1b or 3a), it is a frequently recognized CD8 epitope in HLA-A*01-positive subjects. Viral sequence data reveal that an escape variant is the dominant residue in both genotypes. The predominant Y1444F substitution seemingly impairs binding to the HLA-A*01 molecule, which may have an important impact on the ability to prime a functional CD8 response upon infection. Interestingly, a case of evolution toward the prototype sequence was observed during chronic infection, possibly because the helicase activity of the protein containing the Y1444F substitution is reduced compared to the prototype sequence. Comparison of HCV sequences from Asia and Europe suggests that the frequency of the HLA-A*01 allele in a population may influence the frequency of the escape variant in circulating strains. These data suggest a complex interaction of multiple forces shaping the evolution of HCV in which immune pressure both within the individual and also at the population level in addition to functional constraints are important contributing factors.

Author List

Neumann-Haefelin C, Frick DN, Wang JJ, Pybus OG, Salloum S, Narula GS, Eckart A, Biezynski A, Eiermann T, Klenerman P, Viazov S, Roggendorf M, Thimme R, Reiser M, Timm J

Author

David N. Frick PhD Associate Professor in the Chimistry & Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Adult
Aged
Amino Acid Substitution
Asia
DNA Helicases
Epitopes, T-Lymphocyte
Europe
Evolution, Molecular
Female
HLA-A Antigens
HLA-A1 Antigen
Hepacivirus
Hepatitis C, Chronic
Humans
Male
Middle Aged
Molecular Sequence Data
Phylogeny
Protein Binding
RNA, Viral
Sequence Analysis, DNA
Sequence Homology
Viral Nonstructural Proteins