Cellular immune selection with hepatitis C virus persistence in humans

• Published in: The Journal of experimental medicine Vol. 201; no. 11; pp. 1741 - 1752
• Main Authors: Cox, Andrea L., Mosbruger, Timothy, Mao, Qing, Liu, Zhi, Wang, Xiao-Hong, Yang, Hung-Chih, Sidney, John, Sette, Alessandro, Pardoll, Drew, Thomas, David L., Ray, Stuart C.
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 06.06.2005
• Subjects: Amino Acid Substitution - genetics; Amino Acid Substitution - immunology; CD8-Positive T-Lymphocytes - immunology; Consensus Sequence - genetics; Consensus Sequence - immunology; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Hepacivirus - genetics; Hepacivirus - immunology; Hepatitis C - genetics; Hepatitis C - immunology; Hepatitis C - pathology; Humans; Peptides - genetics; Peptides - immunology; Polymorphism, Genetic - genetics; Polymorphism, Genetic - immunology; Selection, Genetic; T-Lymphocyte Subsets - immunology; Viral Structural Proteins - genetics; Viral Structural Proteins - immunology; Viremia - genetics; Viremia - immunology; Viremia - pathology; Virus Replication - genetics; Virus Replication - immunology
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20050121

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.