ABSTRACT
BACKGROUND: Antigenic variation is an effective way by which viruses evade host immune defense leading to viral persistence. Little is known about the inhibitory mechanisms of viral variants on CD4 T cell functions. RESULTS: Using sythetic peptides of a HLA-DRB1*15-restricted CD4 epitope derived from the non-structural (NS) 3 protein of hepatitis C virus (HCV) and its antigenic variants and the peripheral blood mononuclear cells (PBMC) from six HLA-DRB1*15-positive patients chronically infected with HCV and 3 healthy subjects, the in vitro immune responses and the phenotypes of CD4+CD25+ cells of chronic HCV infection were investigated. The variants resulting from single or double amino acid substitutions at the center of the core region of the Th1 peptide not only induce failed T cell activation but also simultaneously up-regulate inhibitory IL-10, CD25-TGF-ß+ Th3 and CD4+IL-10+ Tr1 cells. In contrast, other variants promote differentiation of CD25+TGF-ß+ Th3 suppressors that attenuate T cell proliferation. CONCLUSIONS: Naturally occuring HCV antigenic mutants of a CD4 epitope can shift a protective peripheral Th1 immune response into an inhibitory Th3 and/or Tr1 response. The modulation of antigenic variants on CD4 response is efficient and extensive, and is likely critical in viral persistence in HCV infection.
Subject(s)
Antigenic Variation , Antigens, Viral/immunology , Hepacivirus/immunology , Hepacivirus/pathogenicity , Immune Evasion , Adult , Amino Acid Substitution/genetics , Antigens, Viral/genetics , CD4-Positive T-Lymphocytes/chemistry , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Female , Hepacivirus/genetics , Humans , Immune Tolerance , Interleukin-2 Receptor alpha Subunit/analysis , Leukocytes, Mononuclear/chemistry , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , Lymphocyte Activation , Male , T-Lymphocyte Subsets/chemistry , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/virologyABSTRACT
BACKGROUND: The association of human leukocyte antigen (HLA) genes with the outcome of hepatitis C virus (HCV) infection may be modified by ethnic and geographical differences. RESULTS: HLA-A, -C, -DRB1 and -DQB1 genotyping were performed in a Midwestern American cohort of 105 HCV infected subjects among which 49 cleared HCV infection and 56 had persistent viral infection. A new protective association of HLA-Cw*05 to HCV infection of all ethnic populations was identified (OR = 0.12, 95% CI = 0.01-0.97, P = 0.03). It was surprising that HLA-A*02 (P for interaction = 0.02) and HLA-DRB1*12 (P for interaction = 0.05) showed statistical interaction with race indicating opposite associations in Caucasians (OR = 2.74 for A*02 and 2.15 for DRB1*12) and non-Caucasians (OR = 0.41 for A*02 and 0.15 for DRB1*12). In addition, HLA-DRB1*01 (OR = 0.26), DQB1*05 (OR = 0.23) and the haplotype DRB1*01-DQB1*05 (OR = 0.19) showed strong associations with viral clearance in Caucasians. The protective associations of A*03 (OR = 0.20) and DQB1*03 (OR = 0.20) were exclusive to non-Caucasians. In contrast, DQB1*02 (OR = 2.56, 95% CI = 1.15-7.71, P = 0.02) and the haplotype DRB1*07-DQB1*02 (OR = 5.25, 95% CI = 1.04-26.6, P = 0.03) were risk markers in Caucasians. CONCLUSION: The associations of HLA-A*02 and HLA-DRB1*12 with HCV infection are opposite with different races. HLA-A*03, Cw*05, DRB1*01, DQB1*03 and DQB1*05 are associated with viral clearance while HLA-DRB1*07 and DQB1*02 are risk markers for viral persistence of HCV infection in Midwestern Americans. These results reveal ethnically and geographically different distribution of HLA-genes which are associated with the outcome of HCV infection.
Subject(s)
HLA Antigens/genetics , Hepatitis C/ethnology , Hepatitis C/genetics , Racial Groups/ethnology , Racial Groups/genetics , Adult , Alleles , Female , Gene Frequency , Geography , Hepacivirus/physiology , Hepatitis C/epidemiology , Humans , Male , Midwestern United States/epidemiology , Midwestern United States/ethnology , Risk Factors , Young AdultABSTRACT
A disturbing feature of hepatitis C virus (HCV) is its long-term persistence in roughly 85% of those infected. Escape mutants may play a major role in HCV persistence. Our previous studies have identified a human leukocyte antigen DRB1*15 (HLA-DRB1*15) restricted Th1 epitope in the HCV NS3 protein, NS3(358-375), and escape variants of this epitope that may emerge under immune selection. Such variants attenuate or fail to stimulate T-cell proliferation. Here we provide data from peripheral blood mononuclear cells derived from four HLA-DRB1*15 patients chronically infected with HCV, and report that naturally occurring single amino acid substitutions in the Th1 epitope NS3(358-375) fail to stimulate proliferation, which is accompanied by a shift in cytokine secretion patterns from one characteristic of a Th1 antiviral responses to a Th2 form. Further, in one patient, we demonstrate that HCV variant peptides can effectively inhibit host polyclonal peripheral T-cell proliferation. We speculate that this phenomenon may be a factor in chronic HCV infection.
