Journal
PLOS GENETICS
Volume 10, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004196
Keywords
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Categories
Funding
- Frederick National Laboratory for Cancer Research [HHSN261200800001E]
- NIH, Frederick National Lab, Center for Cancer Research
- NIAID [R01 AI087145, K24 AI069994, R24 AI067039]
- UCSF/Gladstone CFAR [P30 AI027763]
- UCSF CTSI [UL1 RR024131]
- Center for AIDS Prevention Studies [P30 MH62246]
- Bill and Melinda Gates Foundation
- AIDS Healthcare Foundation
- Harvard University Center for AIDS Research (CFAR), an NIH [P30 AI060354]
- NIAID, NIH
- NCI, NIH
- NICHD, NIH
- NHLBI, NIH
- NIDA, NIH
- NIMH, NIH
- NIA, NIH
- FIC, NIH
- OAR, NIH
- Swiss National Science Foundation
- NIH/NIAID [R01 AI078799, R56 AI098484, R01 AI087452, R01 AI089339]
- MRC
- Wellcome Trust
- AICR
- NIHR Cambridge BRC
- National Institute of Allergy and Infectious Diseases
- National Cancer Institute
- National Heart, Lung, and Blood Institute [U01-AI-35042, UL1-RR025005, U01-AI-35043, U01-AI-35039, U01-AI-35040, U01-AI-35041]
- MRC [G0901682] Funding Source: UKRI
- Medical Research Council [G0901682] Funding Source: researchfish
- Worldwide Cancer Research [13-0074] Funding Source: researchfish
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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.
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