Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery

• Type of Material: Article
• Authors: Jonathan R. Honegger, Nationwide Children's Hospital; Dana Tedesco, Emory University; Jennifer A. Kohout, Nationwide Children's Hospital; Mona R. Prasad, Ohio State University; Aryn A. Price, Emory University; Tera Lindquist, Nationwide Children's Hospital; Samantha Ohmer, Ohio State University; Melissa Moore-Clingenpeel, Nationwide Children's Hospital; Arash Grakoui, Emory University; Christopher M. Walker, Nationwide Children's Hospital
• Language: English
• Date: 2016-09-20
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2016, National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1602337113
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 113
• Issue: 38
• Start Page: 10684
• End Page: 10689
• Grant/Funding Information: This work was supported by US National Institutes of Health Grants R37-AI47367 (to C.M.W.), R56-AI096882 and R01-AI096882 (to C.M.W. and J.R.H.), T32-HD043003 and K12-HD043372 (to J.R.H.), and R01AI070101, 1R21AI118337, and R01AI124680 (to A.G.); The Ohio State University Clinical and Translational Science Award Grants UL1TR001070 and ORIP/OD P51OD011132 (formerly NCRR P51RR000165) to the Yerkes National Primate Research Center; and the Research Institute at Nationwide Children’s Hospital (C.M.W. and J.R.H.).
• Keywords: pregnancy; RISK-FACTORS; Science & Technology; ADAPTIVE IMMUNE-RESPONSES; HCV-RNA LEVELS; SPONTANEOUS CLEARANCE; GENOME-WIDE ASSOCIATION; hepatitis C virus; II ALLELES; HLA-DPB1; Multidisciplinary Sciences; T-cell; ANTI-HCV; IFNL3; GENETIC-VARIATION; HLA-DP EXPRESSION; VIRAL LOAD; Science & Technology - Other Topics
• Research Categories: Biology, Microbiology; Health Sciences, Obstetrics and Gynecology; Health Sciences, Immunology

Abstract

Chronic hepatitis C virus (HCV) infection is characterized by exhaustion of virus-specific T-cells and stable viremia. Pregnancy is an exception. Viremia gradually climbs during gestation but sometimes declines sharply in the months following delivery. Here, we demonstrated that postpartum HCV control was associated with enhanced virus-specific T-cell immunity. Women with viral load declines of at least 1 log10 between the third trimester and 3-mo postpartum exhibited HCV-specific T-cell responses of greater breadth (P = 0.0052) and magnitude (P = 0.026) at 3-mo postpartum than women who failed to control viremia. Moreover, viral dynamics were consistent in women after consecutive pregnancies, suggesting genetic underpinnings. We therefore searched for genetic associations with human leukocyte antigen (HLA) alleles and IFN-λ3 gene (IFNL3) polymorphisms that influence HCV infection outcome. Postpartum viral control was associated with the IFNL3 rs12979860 genotype CC (P = 0.045 at 6 mo) that predicts a positive response to IFN-based therapy. Suppression of virus replication after pregnancy was also strongly influenced by the HLA class II DPB1 locus. HLA-DPB1 alleles are classified by high and low patterns of expression. Carriage of at least one high-expression HLA-DPB1 allele predicted resurgent virus-specific T-cell immunity and viral control at 3-mo postpartum (P = 0.0002). When considered together in multivariable analysis, IFNL3 and HLA-DPB1 independently affected viral control at 3- and 6-mo postpartum. Together, these findings support a model where spontaneous control of HCV such as sometimes follows pregnancy is governed by genetic polymorphisms that affect type III IFN signaling and virus-specific cellular immune responses.