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PLoS Genet. 2014 Mar 6;10(3):e1004196. doi: 10.1371/journal.pgen.1004196. eCollection 2014.

LILRB2 interaction with HLA class I correlates with control of HIV-1 infection.

Author information

  • 1Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America; Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.
  • 2Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.
  • 3Department of Pathology, Cambridge University, Cambridge, United Kingdom.
  • 4Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
  • 5Tissue Typing Laboratories, Addenbrookes Hospital, Cambridge, United Kingdom.
  • 6Northwestern University Medical School, Chicago, Illinois, United States of America.
  • 7Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
  • 8Fielding School of Public Health, University of California at Los Angeles, Los Angeles, California, United States of America.
  • 9University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
  • 10USU Infectious Disease Clinical Research Program, Bethesda, Maryland, United States of America.
  • 11Johns Hopkins University School of Public Health, Baltimore, Maryland, United States of America.
  • 12School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • 13San Francisco Department of Public Health, San Francisco, California, United States of America.
  • 14Division of Cancer Epidemiology & Genetics, NCI, Bethesda, Maryland, United States of America.
  • 15University of California at San Francisco Medical School, San Francisco, California, United States of America.
  • 16Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America; Infectious Disease Division, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
  • 17Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
  • 18Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
  • 19Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
  • 20St George's Medical School, University of London, London, United Kingdom.

Abstract

Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10(-2)). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10(-11)-10(-9)) and African (p = 10(-5)-10(-3)) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement.

PMID:
24603468
[PubMed - indexed for MEDLINE]
PMCID:
PMC3945438
Free PMC Article

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