Differential antigenic hierarchy associated with spontaneous recovery from hepatitis C virus infection: implications for vaccine design.
BACKGROUND
Cellular immune responses play a central role in the control of hepatitis C virus (HCV) infection, and in some individuals the adaptive immune response can spontaneously eradicate HCV infection. The development of vaccine candidates to prevent the spread of this infection remains a top priority; however, understanding the correlates of effective immunological containment is an important prerequisite.


METHODS
Using 750 overlapping peptides, we directly characterized ex vivo total and subgenomic HCV-specific CD4(+) and CD8(+) T cell responses in a large cohort of participants with either chronic infection or spontaneously resolved infection.


RESULTS
In chronic infection, the frequency of total CD4(+) T cells specific for HCV averaged 0.06%, compared with 0.38% in resolved infection. Total HCV-specific CD4(+) and CD8(+) T cell responses were strongly correlated in the setting of spontaneous resolution but not in the setting of viral persistence. NS3 protein-specific responses comprised a significantly greater proportion of the total response in resolved infection than in chronic infection, whereas responses to different regions comprised a larger proportion of responses in chronic infection.


CONCLUSIONS
Because these data comprehensively define the breadth, specificity, and threshold of the T cell response associated with spontaneous recovery from HCV infection, they have important implications in the development of multigenic vaccine candidates for this common infection.
Smyk-Pearson
Susan
S
Division of Gastroenterology and Hepatology, Hepatitis C Center, and Integrated Program in Immunology, University of Colorado Health Sciences Center and National Jewish Hospital, Denver, 80262, USA.
Tester
Ian A
IA
Lezotte
Dennis
D
Sasaki
Anna W
AW
Lewinsohn
David M
DM
Rosen
Hugo R
HR
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D015331:Cohort Studies; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000517:prevention & control*; D018936:Hepatitis C Antigens / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology; D012075:Remission, Spontaneous; D014761:Viral Hepatitis Vaccines / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000276:immunology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000939:Epitopes; D018936:Hepatitis C Antigens; D010446:Peptide Fragments; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases