LILRB 2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection

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). 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 = 10–10) and African (p = 10–10) 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. Citation: Bashirova AA, Martin-Gayo E, Jones DC, Qi Y, Apps R, et al. (2014) LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection. PLoS Genet 10(3): e1004196. doi:10.1371/journal.pgen. 1004196 Editor: Gregory S. Barsh, Stanford University School of Medicine, United States of America Received April 9, 2013; Accepted December 25, 2013; Published March 6, 2014 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. The SCOPE cohort was supported in part by the NIAID (R01 AI087145, K24 AI069994, R24 AI067039), UCSF/Gladstone CFAR (P30 AI027763), the UCSF CTSI (UL1 RR024131), and the Center for AIDS Prevention Studies (P30 MH62246). The International HIV Controllers Study (IHCS), was funded by the Bill and Melinda Gates Foundation, the AIDS Healthcare Foundation and the Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30 AI060354), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH,NIA, FIC and OAR. Members of the International HIV Controllers Study can be found at www.hivcontrollers. org. The Swiss HIV Cohort study (www.shcs.ch) is funded by the Swiss National Science Foundation. XGY was supported by NIH/NIAID R01 AI078799, R56 AI098484, R01 AI087452 and R01 AI089339. JT and DCJ were supported by the MRC, Wellcome Trust and AICR, with partial funding from the NIHR Cambridge BRC. We thank Randy Johnson and George Nelson for helpful discussions. We are grateful to the USU Infectious Disease Clinical Research Program HIV Working Group for collecting and providing clinical data. The MACS clinical data used in this manuscript were collected at: The Johns Hopkins Bloomberg School of Public Health (Joseph Margolick); Howard Brown Health Center and Northwestern University Medical School (John Phair, Steven Wolinsky); University of California, Los Angeles (Roger Detels, Oto Martinez-Maza); University of Pittsburgh (Charles Rinaldo); and Data Analysis Center (Lisa Jacobson). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute; and the National Heart, Lung, and Blood Institute: U01-AI-35042, UL1-RR025005 (GCRC), U01-AI-35043, U01-AI-35039, U01-AI-35040, and U01-AI-35041. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: xyu@partners.org . These authors contributed equally to this work. PLOS Genetics | www.plosgenetics. org 1 March 2014 | Volume 10 | Issue 3 | e1004196