title: Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses.
abstract: Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections. HCV-specific CD8(+) cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms 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. 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. 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.
authors.affiliation: 1] The Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio, USA. [2] Department of Pediatrics, The Ohio State University School of Medicine, Columbus, Ohio, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Honegger
authors.forename: Seungtaek
authors.initials: S
authors.lastname: Kim
authors.forename: Aryn A
authors.initials: AA
authors.lastname: Price
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kohout
authors.forename: Kevin L
authors.initials: KL
authors.lastname: McKnight
authors.forename: Mona R
authors.initials: MR
authors.lastname: Prasad
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
authors.forename: Arash
authors.initials: A
authors.lastname: Grakoui
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Walker
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D005260:Female; D005805:Genes, MHC Class I; D015235:HLA-B Antigens / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008969:Molecular Sequence Data; D009154:Mutation; D036801:Parturition / Q000276:immunology; D049590:Postpartum Period / Q000235:genetics / Q000276:immunology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000235:genetics / Q000276:immunology* / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D014766:Viremia / Q000150:complications / Q000235:genetics / Q000276:immunology
chemical_list: D015235:HLA-B Antigens