title: LILRB2 interaction with HLA class I correlates with control of HIV-1 infection.
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.
authors.affiliation: 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.
authors.forename: Arman A
authors.initials: AA
authors.lastname: Bashirova
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.
authors.forename: Enrique
authors.initials: E
authors.lastname: Martin-Gayo
authors.affiliation: Department of Pathology, Cambridge University, Cambridge, United Kingdom.
authors.forename: Des C
authors.initials: DC
authors.lastname: Jones
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Apps
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Burke
authors.affiliation: Tissue Typing Laboratories, Addenbrookes Hospital, Cambridge, United Kingdom.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Taylor
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.
authors.forename: Jerome
authors.initials: J
authors.lastname: Rogich
authors.affiliation: Northwestern University Medical School, Chicago, Illinois, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Wolinsky
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Bream
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Priya
authors.initials: P
authors.lastname: Duggal
authors.affiliation: Fielding School of Public Health, University of California at Los Angeles, Los Angeles, California, United States of America.
authors.forename: Shehnaz
authors.initials: S
authors.lastname: Hussain
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Martinson
authors.affiliation: USU Infectious Disease Clinical Research Program, Bethesda, Maryland, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Weintrob
authors.affiliation: Johns Hopkins University School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirk
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.affiliation: San Francisco Department of Public Health, San Francisco, California, United States of America.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Buchbinder
authors.affiliation: Division of Cancer Epidemiology & Genetics, NCI, Bethesda, Maryland, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.affiliation: University of California at San Francisco Medical School, San Francisco, California, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: 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.
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.affiliation: Department of Pathology, Cambridge University, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
authors.affiliation: Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.affiliation: Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: St George's Medical School, University of London, London, United Kingdom.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Allen
authors.affiliation: 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.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
mesh_terms: D000483:Alleles; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology; D019562:Viral Load / Q000235:genetics / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic