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BACKGROUND & AIMS: Broadly reactive neutralizing antibodies (nAbs) and multispecific T-cell responses are generated during chronic hepatitis C virus (HCV) infection and yet fail to clear the virus. This study investigated the development of autologous nAb and HCV-glycoprotein-specific T-cell responses and their effects on viral sequence evolution during chronic infection in order to understand the reasons for their lack of effectiveness. METHODS: Numerous E1E2 sequences were amplified and sequenced from serum samples collected over a 26-year period from patient H, a uniquely well-characterized, chronically infected individual. HCV pseudoparticles (HCVpp) expressing the patient-derived glycoproteins were generated and tested for their sensitivity to neutralization by autologous and heterologous serum antibodies. RESULTS: A strain-specific nAb response developed early in infection (8 weeks postinfection), whereas cross-reactive antibodies able to neutralize HCVpp-bearing heterologous glycoproteins developed late in infection (>33 wk postinfection). The humoral response continuously failed to neutralize viruses bearing autologous glycoprotein sequences that were present in the serum at a given time. The amplified glycoprotein sequences displayed high variability, particularly in regions corresponding to defined linear B-cell epitopes. Mutations in defined neutralizing epitopes were associated with a loss of recognition by monoclonal antibodies against these epitopes and with decreased neutralization of corresponding HCVpp. Viral escape from CD4 and CD8 T-cell responses also was shown for several novel epitopes throughout the glycoprotein region. CONCLUSIONS: During chronic infection HCV is subjected to selection pressures from both humoral and cellular immunity, resulting in the continuous generation of escape variants.

Original publication

DOI

10.1053/j.gastro.2006.12.008

Type

Journal article

Journal

Gastroenterology

Publication Date

02/2007

Volume

132

Pages

667 - 678

Keywords

Amino Acid Sequence, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Line, Cross Reactions, Epitopes, T-Lymphocyte, Hepacivirus, Hepatitis C Antibodies, Hepatitis C, Chronic, Humans, Immunity, Cellular, Immunity, Innate, Molecular Sequence Data, Mutation, Neutralization Tests, Polymorphism, Genetic, RNA, Viral, T-Lymphocytes, Time Factors, Viral Envelope Proteins, Virion