Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery.
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.
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.
Jonathan R
0000-0002-3181-0554
JR
Honegger
Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
Dana
D
Tedesco
The Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205;
Jennifer A
JA
Kohout
Department of Obstetrics and Gynecology, The Ohio State University School of Medicine, Columbus, OH 43210;
Mona R
MR
Prasad
Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
Aryn A
AA
Price
The Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205;
Tera
T
Lindquist
Medical Scientist Training Program, The Ohio State University, Columbus, OH 43210; Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210;
Samantha
S
Ohmer
Biostatistics Core, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205;
Melissa
M
Moore-Clingenpeel
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.
Arash
A
Grakoui
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;
Christopher M
CM
Walker
D000328:Adult; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D005838:Genotype; D059868:HLA-DP beta-Chains / Q000235:genetics*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000276:immunology / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology; D033261:Maternal-Fetal Relations; D020641:Polymorphism, Single Nucleotide; D049590:Postpartum Period; D011247:Pregnancy; D013601:T-Lymphocytes / Q000276:immunology; D019562:Viral Load / Q000276:immunology; D014779:Virus Replication / Q000235:genetics
D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; C116468:IFIT3 protein, human; D047908:Intracellular Signaling Peptides and Proteins
HLA-DPB1; IFNL3; T-cell; hepatitis C virus; pregnancy