Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes

TY - JOUR

T1 - Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes

AU - Schulze zur Wiesch, Julian

AU - Lauer, Georg M

AU - Day, Cheryl L

AU - Kim, Arthur Y

AU - Ouchi, Kei

AU - Duncan, Jared E

AU - Wurcel, Alysse G

AU - Timm, Joerg

AU - Jones, Andrea M

AU - Mothe, Bianca

AU - Allen, Todd M

AU - McGovern, Barbara

AU - Lewis-Ximenez, Lia

AU - Sidney, John

AU - Sette, Alessandro

AU - Chung, Raymond T

AU - Walker, Bruce D

PY - 2005/9/15

Y1 - 2005/9/15

N2 - A vigorous hepatitis C virus (HCV)-specific Th cell response is regarded as essential to the immunological control of HCV viremia. The aim of this study was to comprehensively define the breadth and specificity of dominant HCV-specific CD4(+) T cell epitopes in large cohorts of subjects with chronic and spontaneously resolved HCV viremia. Following in vitro stimulation of PBMC, HCV-specific cell cultures from each subject were screened with an overlapping panel of synthetic 20-mer peptides spanning the entire HCV polyprotein. Of 22 subjects who spontaneously controlled HCV viremia, all recognized at least one of a group of six epitopes situated within the nonstructural (NS) proteins NS3, NS4, and NS5, each of which was detected by >30% of subjects, but most subjects recognized additional, more heterogeneous specificities. In contrast, none of the most frequently targeted epitopes was detected by >5% of persons with chronic infection. The most frequently recognized peptides showed promiscuous binding to multiple HLA-DR molecules in in vitro binding assays and were restricted by different HLA-DR molecules in functional assays in different persons. These data demonstrate that predominant CD4(+) T cell epitopes in persons with resolved HCV infection are preferentially located in the nonstructural proteins and are immunogenic in the context of multiple class II molecules. This comprehensive characterization of CD4(+) T cell epitopes in resolved HCV infection provides important information to facilitate studies of immunopathogenesis and HCV vaccine design and evaluation.

AB - A vigorous hepatitis C virus (HCV)-specific Th cell response is regarded as essential to the immunological control of HCV viremia. The aim of this study was to comprehensively define the breadth and specificity of dominant HCV-specific CD4(+) T cell epitopes in large cohorts of subjects with chronic and spontaneously resolved HCV viremia. Following in vitro stimulation of PBMC, HCV-specific cell cultures from each subject were screened with an overlapping panel of synthetic 20-mer peptides spanning the entire HCV polyprotein. Of 22 subjects who spontaneously controlled HCV viremia, all recognized at least one of a group of six epitopes situated within the nonstructural (NS) proteins NS3, NS4, and NS5, each of which was detected by >30% of subjects, but most subjects recognized additional, more heterogeneous specificities. In contrast, none of the most frequently targeted epitopes was detected by >5% of persons with chronic infection. The most frequently recognized peptides showed promiscuous binding to multiple HLA-DR molecules in in vitro binding assays and were restricted by different HLA-DR molecules in functional assays in different persons. These data demonstrate that predominant CD4(+) T cell epitopes in persons with resolved HCV infection are preferentially located in the nonstructural proteins and are immunogenic in the context of multiple class II molecules. This comprehensive characterization of CD4(+) T cell epitopes in resolved HCV infection provides important information to facilitate studies of immunopathogenesis and HCV vaccine design and evaluation.

KW - Cells, Cultured

KW - Chronic Disease

KW - Epitopes, T-Lymphocyte/immunology

KW - HLA-DR Antigens/immunology

KW - Hepatitis C/immunology

KW - Histocompatibility Antigens Class II/immunology

KW - Humans

KW - Immunodominant Epitopes/immunology

KW - Remission, Spontaneous

KW - T-Cell Antigen Receptor Specificity

KW - T-Lymphocytes, Helper-Inducer/immunology

KW - Viral Nonstructural Proteins/immunology

KW - Viremia/immunology

U2 - 10.4049/jimmunol.175.6.3603

DO - 10.4049/jimmunol.175.6.3603

M3 - SCORING: Journal article

C2 - 16148104

VL - 175

SP - 3603

EP - 3613

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 6

ER -