Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses

Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV)(1). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies(2) and accounts for most new childhood infections(1,3). HCV-specific CD8+ cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections(4-6), but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition(7-9). Increased HCV replication during pregnancy(10,11) suggests that maternofetal immune tolerance mechanisms(12) may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses(13). CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply(14). Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.