Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo.
OBJECTIVE
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.
von Hahn
Thomas
T
Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10021, USA. vonhaht@rockefeller.edu
Yoon
Joo Chun
JC
Alter
Harvey
H
Rice
Charles M
CM
Rehermann
Barbara
B
Balfe
Peter
P
McKeating
Jane A
JA
D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000097:blood*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D007113:Immunity, Innate; D008969:Molecular Sequence Data; D009154:Mutation; D009500:Neutralization Tests; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000097:blood; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014771:Virion / Q000276:immunology
C087035:E1 protein, Hepatitis C virus; D018984:Epitopes, T-Lymphocyte; D018937:Hepatitis C Antibodies; D012367:RNA, Viral; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus