PMID- 27601657 OWN - NLM STAT- MEDLINE DCOM- 20180125 LR - 20220316 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 113 IP - 38 DP - 2016 Sep 20 TI - Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery. PG - 10684-9 LID - 10.1073/pnas.1602337113 [doi] AB - 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-lambda3 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. FAU - Honegger, Jonathan R AU - Honegger JR AUID- ORCID: 0000-0002-3181-0554 AD - The Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205; Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH 43205; jonathan.honegger@nationwidechildrens.org. FAU - Tedesco, Dana AU - Tedesco D AD - Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; FAU - Kohout, Jennifer A AU - Kohout JA AD - The Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205; FAU - Prasad, Mona R AU - Prasad MR AD - Department of Obstetrics and Gynecology, The Ohio State University School of Medicine, Columbus, OH 43210; FAU - Price, Aryn A AU - Price AA AD - Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; FAU - Lindquist, Tera AU - Lindquist T AD - The Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205; FAU - Ohmer, Samantha AU - Ohmer S AD - Medical Scientist Training Program, The Ohio State University, Columbus, OH 43210; Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210; FAU - Moore-Clingenpeel, Melissa AU - Moore-Clingenpeel M AD - Biostatistics Core, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205; FAU - Grakoui, Arash AU - Grakoui A AD - Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322. FAU - Walker, Christopher M AU - Walker CM AD - The Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205; Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH 43205; LA - eng GR - UL1 TR001070/TR/NCATS NIH HHS/United States GR - T32 HD043003/HD/NICHD NIH HHS/United States GR - P51 OD011132/OD/NIH HHS/United States GR - P51 RR000165/RR/NCRR NIH HHS/United States GR - R01 AI070101/AI/NIAID NIH HHS/United States GR - R56 AI096882/AI/NIAID NIH HHS/United States GR - R01 AI096882/AI/NIAID NIH HHS/United States GR - R01 AI126890/AI/NIAID NIH HHS/United States GR - R21 AI118337/AI/NIAID NIH HHS/United States GR - K12 HD043372/HD/NICHD NIH HHS/United States GR - R37 AI047367/AI/NIAID NIH HHS/United States GR - R01 AI124680/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20160906 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (HLA-DP beta-Chains) RN - 0 (HLA-DPB1 antigen) RN - 0 (IFIT3 protein, human) RN - 0 (Intracellular Signaling Peptides and Proteins) SB - IM CIN - doi: 10.1073/pnas.1602319113 MH - Adult MH - Female MH - Gene Expression Regulation/immunology MH - Genotype MH - HLA-DP beta-Chains/*genetics MH - Hepacivirus/genetics/*immunology/pathogenicity MH - Hepatitis C, Chronic/*genetics/immunology/virology MH - Humans MH - Immunity, Cellular/*genetics MH - Intracellular Signaling Peptides and Proteins/*genetics/immunology MH - Maternal-Fetal Relations MH - Polymorphism, Single Nucleotide MH - Postpartum Period MH - Pregnancy MH - T-Lymphocytes/immunology MH - Viral Load/immunology MH - Virus Replication/genetics PMC - PMC5035892 OTO - NOTNLM OT - HLA-DPB1 OT - IFNL3 OT - T-cell OT - hepatitis C virus OT - pregnancy COIS- The authors declare no conflict of interest. EDAT- 2016/09/08 06:00 MHDA- 2018/01/26 06:00 PMCR- 2017/03/20 CRDT- 2016/09/08 06:00 PHST- 2016/09/08 06:00 [entrez] PHST- 2016/09/08 06:00 [pubmed] PHST- 2018/01/26 06:00 [medline] PHST- 2017/03/20 00:00 [pmc-release] AID - 1602337113 [pii] AID - 201602337 [pii] AID - 10.1073/pnas.1602337113 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2016 Sep 20;113(38):10684-9. doi: 10.1073/pnas.1602337113. Epub 2016 Sep 6.