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). Vertical transmission occurs in 3–5% of cases(2) and accounts for most new childhood HCV infections(1,3). HCV-specific CD8(+) cytotoxic T-lymphocytes (CTLs) play a vital role in the clearance of acute infections(4–6), but in the 60–80% of infections that persist these cells become functionally exhausted or select 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 selection pressure on persistent viruses. To assess this possibility, we characterized the circulating viral quasispecies during and after consecutive pregnancies. This revealed a loss of some escape mutations in class I epitopes in pregnancy associated with emergence of more fit viruses(13). CTL selection pressure was reimposed after childbirth, when escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply(14). Importantly, viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that immunoregulatory changes of pregnancy reduce CTL selection pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.