Cellular immune selection with hepatitis C virus persistence in humans

Andrea L. Cox, Timothy Mosbruger, Qing Mao, Zhi Liu, Xiao Hong Wang, Hung Chih Yang, John Sidney, Alessandro Sette, Drew Pardoll, David L. Thomas, Stuart C. Ray

Research output: Contribution to journalArticlepeer-review

Abstract

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. JEM

Original languageEnglish (US)
Pages (from-to)1741-1752
Number of pages12
JournalJournal of Experimental Medicine
Volume201
Issue number11
DOIs
StatePublished - Jun 6 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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