No evidence for viral escape mutations in immunodominant CD4 HCV-specific epitopes

Hepatitis C virus (HCV) infection provides a valuable model for studying immune responses under viral persistence and clearance. About 70% of infections become chronic, while 30% resolve spontaneously. Viral adaptation to CD8 T cell pressure is linked to viral persistence. However, immune escape in CD4 T cells is less understood.

This study aimed to compare HCV-specific CD4 T cells in patients with chronic infection, patients who resolved HCV via direct-acting antiviral (DAA) therapy, and individuals with spontaneous resolution, including potential CD4 immune escape mechanisms.

Therefore, we analyzed HCV-specific CD4 T cells using MHC class II tetramers in peripheral blood mononuclear cells (PBMCs) from 139 patients with chronic and spontaneously resolved HCV. CD4 T cells in resolved individuals showed higher CD127 expression and lower CD95 and PD-1 expression compared to chronic HCV patients. For in-depth analysis of immunodominant viral epitopes, viral isolates were sequenced, and mutations were analyzed in relation to HLA-DRB1 alleles using Fisher’s exact test. Found mutations were genotype-specific and not associated with HLA-DRB1-alleles. CD4 T cell recognition was tested using epitope-specific T cell clones stimulated with mutated and non-mutated epitopes, followed by cytokine secretion analysis. Importantly, HCV-specific CD4 T cell clones recognized both mutated and non-mutated epitopes equally.

In conclusion, we identified phenotypic differences in CD4 T cells between chronic and resolved HCV cases. There was no evidence for viral escape in the analyzed CD4 epitopes.

These findings offer important insights into the immune mechanisms of HCV persistence and resolution, with potential implications for CD4 T cell-targeted therapies.

Publication History

Article published online:
20 January 2025