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

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

Author information

1
Cancer 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.
2
Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.
3
Department of Pathology, Cambridge University, Cambridge, United Kingdom.
4
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
5
Tissue Typing Laboratories, Addenbrookes Hospital, Cambridge, United Kingdom.
6
Northwestern University Medical School, Chicago, Illinois, United States of America.
7
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
8
Fielding School of Public Health, University of California at Los Angeles, Los Angeles, California, United States of America.
9
University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
10
USU Infectious Disease Clinical Research Program, Bethesda, Maryland, United States of America.
11
Johns Hopkins University School of Public Health, Baltimore, Maryland, United States of America.
12
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
13
San Francisco Department of Public Health, San Francisco, California, United States of America.
14
Division of Cancer Epidemiology & Genetics, NCI, Bethesda, Maryland, United States of America.
15
University of California at San Francisco Medical School, San Francisco, California, United States of America.
16
Ragon 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.
17
Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
18
Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
19
Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
20
St 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
PMCID:
PMC3945438
DOI:
10.1371/journal.pgen.1004196
[Indexed for MEDLINE]
Free PMC Article

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