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.

Paediatric HIV infection: the potential for cure

“…Indeed, it has been proposed in adult studies that HLA class I molecules such as HLA-B*35 that are associated with rapid disease progression in adults may actively facilitate post-treatment control 14 . A possible mechanism is suggested by the fact that HLA-B*35 and HLA-B*45:01 bind the leukocyte immunoglobulin-like receptor LILRB2 with high avidity, whereas protective HLA alleles such as HLA-B*27/57/58:01 bind LILRB2 with low avidity 107 . LILRB2 is expressed on cells of the myeloid lineage, such as conventional dendritic cells, and high avidity HLA class I binding by LILRB2 inhibits dendritic cell function.…”

Functional and genetic diversity of leukocyte immunoglobulin-like receptor and implication for disease associations

“…39 The strength of LILRB2 binding to HLA class I alleles is correlated with odds ratios for corresponding HLA alleles determined by comparing HIV-1 controllers with noncontrollers. 40 Moreover, LILRB2 recognizes native CD1d on the cell surface and in the endosomal and lysosomal compartments to block the loading of lipid antigen onto CD1d. 41 In addition to these HLA or HLA-like molecules, LILRB2 recognizes non-HLA ligands, suggesting that LILRB2 has crucial roles in diverse biological functions.…”

Human genetic variation in HIV disease

“…Bashirova et al [8] examined the effects of interaction of leukocyte immunoglobulin-like receptors (LILRB1 and LILRB2, HLA-interacting inhibitory receptors present on the surface of myeloid cells) and HLA class I alleles on viral load. In particular, the variable impact of alleles of classical class I HLA genes (primarily HLA-B) on patient viral load (VL) has been thoroughly investigated.…”