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

• Type of Material: Article
• Authors: Jonathan R. Honegger, Nationwide Children’s Hospital; Seungtaek Kim, University of North Carolina; Aryn A. Price, Emory University; Jennifer A. Kohout, Nationwide Children’s Hospital; Kevin L. McKnight, University of North Carolina; Mona R. Prasad, Ohio State University; Stanley M. Lemon, University of North Carolina; Arash Grakoui, Emory University; Christopher M. Walker, Nationwide Children’s Hospital
• Language: English
• Date: 2013-11-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/nm.3351
• Title of Journal or Parent Work: Nature Medicine
• ISSN: 1078-8956
• Volume: 19
• Issue: 11
• Start Page: 1529
• End Page: +
• Grant/Funding Information: This work was supported by the US National Institutes of Health (R37-AI47367 to C.W; R56-AI096882 and R01-AI096882 to C.W and J.H.; RO1-DA024565 and R01-AI95690 to S.L.; R01-AI070101 and R01-DK083356 to A.G.; T32-HD043003 and K12-HD043372 to J.H.; and the Yerkes Research Center Base Grant P51RR-000165 (A.G.)); The Research Institute at Nationwide Children’s Hospital (C.W. and J.H.); and the University of North Carolina University Cancer Research Fund (S.L.).
• Keywords: Cell Biology; T-CELL RESPONSE; Science & Technology; RNA; MOTHER; TRANSMISSION; PROTEINS; RISK-FACTORS; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; HEPATITIS-C-VIRUS; VIRAL EVOLUTION; Research & Experimental Medicine; EXPRESSION; EPITOPES; Medicine, Research & Experimental
• Research Categories: Health Sciences, Obstetrics and Gynecology; Biology, Virology; Biology, Cell

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.