Hepatitis C viral variants bear signatures of de novo CD8+ T cell and antibody pressure after spontaneous postpartum viral suppression

Progression to chronic hepatitis C virus (HCV) infection entails loss of HCV-specific CD4+ T cell help, emergence of viral variants that escape recognition by CD8+ T cells and neutralizing antibodies, and exhaustion of CD8+ T cells targeting remaining intact epitopes. Once chronic infection has been established, it is generally lifelong without treatment. However, in some chronically infected women, a surprising postpartum viral load decline has been linked to resurgent functional HCV-specific CD4+ helper T cells. A minority of women even spontaneously clear long-standing chronic infection postpartum. To test whether restored T cell help boosts HCV-specific CD8+ T cell or antibody responses in women with postpartum viral control, we performed serial near-full-length deep sequencing of HCV genomes to assess evolution of viral MHC class I epitopes and antibody epitopes in nine women with significant postpartum viral declines (≥ 1 log 10 at 3 mo postpartum, “controllers”) and 12 with more stable levels (“noncontrollers”). Although not associated with mutations arising early postpartum, at 12 to 24 mo postpartum, viral control was strongly associated with amino acid mutations in epitopes predicted to be targeted by CD8+ T cells and neutralizing antibodies. Plasma from controllers also demonstrated a postpartum increase in neutralization of multiple HCV strains. Together, these findings support the hypothesis that postpartum viral control is mediated by CD8+ T cell and antibody pressure.