The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published 6 June 2005. doi:10.1084/jem.20050121
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 11, 1741-1752
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*Nucleotide*Protein
*Substance via MeSH
Medline Plus Health Information
*Hepatitis C
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ARTICLE

 Cellular immune selection with hepatitis C virus persistence in humans

Andrea L. Cox1,2, Timothy Mosbruger1, Qing Mao1, Zhi Liu1, Xiao-Hong Wang1, Hung-Chih Yang1, John Sidney6, Alessandro Sette6, Drew Pardoll1,2,3,4, David L. Thomas1,5, and Stuart C. Ray1

1 Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231
2 Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231
3 Department of Molecular Biology and Genetics, Johns Hopkins Medical Institutions, Baltimore, MD 21231
4 Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231
5 Department of Epidemiology, Johns Hopkins Medical Institutions, Baltimore, MD 21231
6 La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

CORRESPONDENCE Andrea L. Cox: acox{at}jhmi.edu

Hepatitis C virus (HCV) infection frequently persists despite substantial virus-specific cellular immune responses. To determine if immunologically driven sequence variation occurs with HCV persistence, we coordinately analyzed sequence evolution and CD8+ T cell responses to epitopes covering the entire HCV polyprotein in subjects who were followed prospectively from before infection to beyond the first year. There were no substitutions in T cell epitopes for a year after infection in a subject who cleared viremia. In contrast, in subjects with persistent viremia and detectable T cell responses, we observed substitutions in 69% of T cell epitopes, and every subject had a substitution in at least one epitope. In addition, amino acid substitutions occurred 13-fold more often within than outside T cell epitopes (P < 0.001, range 5–38). T lymphocyte recognition of 8 of 10 mutant peptides was markedly reduced compared with the initial sequence, indicating viral escape. Of 16 nonenvelope substitutions that occurred outside of known T cell epitopes, 8 represented conversion to consensus (P = 0.015). These findings reveal two distinct mechanisms of sequence evolution involved in HCV persistence: viral escape from CD8+ T cell responses and optimization of replicative capacity.

Abbreviations used: E1, envelope glycoprotein 1; E2, envelope glycoprotein 2; HCV, hepatitis C virus; HVR1, hypervariable region 1; SFC, spot-forming colony.


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