LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions

J Clin Invest. 2018 Apr 2;128(4):1523-1537. doi: 10.1172/JCI96174. Epub 2018 Mar 12.


UL18 is a human CMV (HCMV) MHC class I (MHCI) homolog that efficiently inhibits leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1)+ NK cells. We found an association of LILRB1 polymorphisms in the regulatory regions and ligand-binding domains with control of HCMV in transplant patients. Naturally occurring LILRB1 variants expressed in model NK cells showed functional differences with UL18 and classical MHCI, but not with HLA-G. The altered functional recognition was recapitulated in binding assays with the binding domains of LILRB1. Each of 4 nonsynonymous substitutions in the first 2 LILRB1 immunoglobulin domains contributed to binding with UL18, classical MHCI, and HLA-G. One of the polymorphisms controlled addition of an N-linked glycan, and that mutation of the glycosylation site altered binding to all ligands tested, including enhancing binding to UL18. Together, these findings indicate that specific LILRB1 alleles that allow for superior immune evasion by HCMV are restricted by mutations that limit LILRB1 expression selectively on NK cells. The polymorphisms also maintained an appropriate interaction with HLA-G, fitting with a principal role of LILRB1 in fetal tolerance.

Keywords: Genetic variation; Immunology; Infectious disease; Innate immunity; Organ transplantation.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD* / genetics
  • Antigens, CD* / immunology
  • Capsid Proteins* / genetics
  • Capsid Proteins* / immunology
  • Cell Line
  • Cytomegalovirus Infections* / genetics
  • Cytomegalovirus Infections* / immunology
  • Cytomegalovirus Infections* / pathology
  • Cytomegalovirus* / genetics
  • Cytomegalovirus* / immunology
  • Female
  • Genetic Predisposition to Disease*
  • HLA-G Antigens* / genetics
  • HLA-G Antigens* / immunology
  • Humans
  • Killer Cells, Natural / immunology
  • Leukocyte Immunoglobulin-like Receptor B1* / genetics
  • Leukocyte Immunoglobulin-like Receptor B1* / immunology
  • Male
  • Organ Transplantation*
  • Polymorphism, Genetic*


  • Antigens, CD
  • Capsid Proteins
  • HLA-G Antigens
  • LILRB1 protein, human
  • Leukocyte Immunoglobulin-like Receptor B1
  • VP23 protein, Human herpesvirus 1

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