LILRB2 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 = 10-2). 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

Spearman correlation between LILRB2 binding strength and mVL in HIV-1-infected individuals.

<p>Spearman correlation between LILRB2 binding strength and mVL in HIV-1-infected individuals.</p

Effect of LILRB2-HLA binding strength and individual class I alleles on viral control (controllers vs. non-controllers) in white patients.

<p>Logistic regression model with stepwise selection included all <i>HLA</i> class I alleles with phenotypic frequencies of >2% and one of the A, B, C or ABC binding scores at a time. The results are shown for the p<0.05 cut-off. The C binding score did not stay in the model. ORs for binding scores reflect a change of 0.1 units.</p>1<p>stayed in the model with the p<0.01 cut-off but not with the p<0.001 cut-off.</p>2<p>stayed in the model with the p<0.01 and p<0.001 cut-offs.</p

LILRB2-HLA binding score variations in 2900 white (A) and 1490 black (B) patients.

<p>A, B and C binding scores represent the sum of the binding scores for two alleles of the corresponding <i>HLA</i> class I locus. ABC binding score represents the sum of the locus-specific binding scores with the C scores counted at 1/10 level. Alleles with undefined scores were assigned the average of the scores for a given locus. Box and Whisker plots reflect median, the 25% and 75% percentiles and the minimum and maximum of all data.</p

LILRB2 binding strength and odds ratios for viral load control for individual <i>HLA-B</i> alleles.

<p>The data plotted includes only alleles with significant association (p<0.05) for white (A) and black (B) patients in a univariate analysis for each <i>HLA-B</i> allele. Spearman correlation coefficient and p values are indicated.</p