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.