Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1.
Ontology highlight
ABSTRACT:
SUBMITTER: Martin MP
PROVIDER: S-EPMC4135476 | biostudies-literature | 2007 Jun
REPOSITORIES: biostudies-literature
Publications
Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1.
Martin Maureen P MP Qi Ying Y Gao Xiaojiang X Yamada Eriko E Martin Jeffrey N JN Pereyra Florencia F Colombo Sara S Brown Elizabeth E EE Shupert W Lesley WL Phair John J Goedert James J JJ Buchbinder Susan S Kirk Gregory D GD Telenti Amalio A Connors Mark M O'Brien Stephen J SJ Walker Bruce D BD Parham Peter P Deeks Steven G SG McVicar Daniel W DW Carrington Mary M
Nature genetics 20070513 6
Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data corr ...[more]
Similar Datasets
Project description:Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells-upregulated in the post-HCT environment-signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity. We hypothesized that varied strengths of inhibition among subtypes of the ubiquitous KIR3DL1 and its cognate ligand, HLA-B, would titrate NK reactivity against acute myelogenous leukemia (AML). Patients and Methods By using an algorithm that was based on polymorphism-driven expression levels and specificities, we predicted and tested inhibitory and cytotoxic NK potential on the basis of KIR3DL1/HLA-B subtype combinations in vitro and evaluated their impact in 1,328 patients with AML who underwent HCT from 9/10 or 10/10 HLA-matched unrelated donors. Results Segregated by KIR3DL1 subtype, NK cells demonstrated reproducible patterns of strong, weak, or noninhibition by target cells with defined HLA-B subtypes, which translated into discrete cytotoxic hierarchies against AML. In patients, KIR3DL1 and HLA-B subtype combinations that were predictive of weak inhibition or noninhibition were associated with significantly lower relapse (hazard ratio [HR], 0.72; P = .004) and overall mortality (HR, 0.84; P = .030) compared with strong inhibition combinations. The greatest effects were evident in the high-risk group of patients with all KIR ligands (relapse: HR, 0.54; P < .001; and mortality: HR, 0.74; P < .008). Beneficial effects of weak and noninhibiting KIR3DL1 and HLA-B subtype combinations were separate from and additive to the benefit of donor activating KIR2DS1. Conclusion Consideration of KIR3DL1-mediated inhibition in donor selection for HLA-matched HCT may achieve superior graft versus leukemia effects, lower risk for relapse, and an increase in survival among patients with AML.
| S-EPMC5501362 | biostudies-literature
Project description:NK cells recognize self-HLA via killer Ig-like receptors (KIR). Homeostatic HLA expression signals for inhibition via KIR, and downregulation of HLA, a common consequence of viral infection, allows NK activation. Like HLA, KIR are highly polymorphic, and allele combinations of the most diverse receptor-ligand pair, KIR3DL1 and HLA-B, correspond to hierarchical HIV control. We used primary cells from healthy human donors to demonstrate how subtype combinations of KIR3DL1 and HLA-B calibrate NK education and their consequent capacity to eliminate HIV-infected cells. High-density KIR3DL1 and Bw4-80I partnerships endow NK cells with the greatest reactivity against HLA-negative targets; NK cells exhibiting the remaining KIR3DL1/HLA-Bw4 combinations demonstrate intermediate responsiveness; and Bw4-negative KIR3DL1(+) NK cells are poorly responsive. Cytotoxicity against HIV-infected autologous CD4(+) T cells strikingly correlated with reactivity to HLA-negative targets. These findings suggest that the programming of NK effector function results from defined features of receptor and ligand subtypes. KIR3DL1 and HLA-B subtypes exhibit an array of binding strengths. Like KIR3DL1, subtypes of HLA-Bw4 are expressed at distinct, predictable membrane densities. Combinatorial permutations of common receptor and ligand subtypes reveal binding strength, receptor density, and ligand density to be functionally important. These findings have immediate implications for prognosis in patients with HIV infection. Furthermore, they demonstrate how features of KIR and HLA modified by allelic variation calibrate NK cell reactive potential.
| S-EPMC4868784 | biostudies-literature
Project description:Carriage of the genetic combination encoding a high expression inhibitory Killer Immunoglobulin-like Receptor (KIR)3DL1 with its ligand, HLA-B*57 (*h/*y+B*57) is associated with slower time to AIDS and better HIV viral load control than being a Bw6 homozygote (Bw6hmz). Natural Killer (NK) cells from *h/*y+B*57 carriers receive potent educational signals through HLA-B*57 KIR3DL1 ligation leading to high functional potential. NK cells from Bw6hmz are not educated through KIR3DL1 because Bw6 antigens do not interact with this inhibitory receptor. To better understand the impact of KIR/HLA combinations on NK cell mediated anti-viral activity we measured NK cell mediated inhibition of HIV replication in autologous infected CD4 (iCD4) cells by assessing the frequency of p24 positive CD4 targets and supernatant levels of HIV p24 longitudinally in the presence versus absence of NK cells. Forty-seven HIV uninfected subjects were studied, including carriers of *h/*y+B*57, a low expression KIR3DL1 genotype with HLA-B*57 termed *l/*x+B*57, a genotype designated 3DS1+*80I and Bw6hmz. NK cells from *h/*y+B*57 carriers, like those from 3DS1+*80I subjects, inhibited HIV replication in autologous iCD4 cells better than those from Bw6hmz and *l/*x+B*57 carriers. Cell contact between NK and iCD4 cells activated NK cells to inhibit viral replication in a non-contact dependent fashion through secretion of CC-chemokines. iCD4 stimulated NK cells from *h/*y+B*57 and 3DS1+*80I carriers produced higher levels of CC-chemokines than those from Bw6hmz or *l/*x+B*57 carriers. Higher levels of CC-chemokines were produced by KIR3DL1(+) than KIR3DL1(-) NK cells. We conclude that NK-mediated inhibition of viral replication in autologous iCD4 cells is partially due to a block at the level of HIV entry into new targets by secreted CC-chemokines.
| S-EPMC3894215 | biostudies-literature
Project description:ObjectivesThe aim of this study was to develop a small interfering RNA (siRNA) against the expression of KIR3DL1 receptor on natural killer (NK) cells, in order to promote the ability of NK cells to destroy human immunodeficiency virus (HIV)-infected cells and thus prevent failure of siRNA therapy targeting human immunodeficiency virus type 1 (HIV-1) virus among HIV-1 infected patients in vitro.MethodsA siRNA targeting KIR3DL1 was synthesized and then modified with cholesterol, methylene, and sulfate. The inhibitory action of the siRNAs on primary cultured NK cells was detected. The amount of IFN-γ and TNF-α secretions in NK cells was measured. The intended functions of NK cells in vitro were analyzed by CFSE and PI methods.ResultsThere were no significant differences in inhibiting the expression of KIR3DL1 on NK cells between the modified and unmodified siRNAs, while inhibition by each of them differed significantly from controls. The amount of IFN-γ and TNF-α secretions in the NK cells was abundant due to unsuccessful expression of KIR3DL1 on NK cells, which further promoted function of the NK cells.ConclusionThe siRNA against KIR3DL1 could enhance the ability of the NK cells to kill the HIV-1 infected cells in vitro and successfully prevented the failure of siRNA therapy targeting the HIV-1 virus. Therefore, it can act as a potential gene therapeutic agent among HIV-1 infected people.
| S-EPMC4043363 | biostudies-literature
Project description:We investigated the role of the KIR loci and their HLA class I ligands in a large cohort of African American multiple sclerosis (MS) patients (N=907) and controls (N=1456). No significant differences in carrier frequencies for any KIR locus or haplotype were observed between cases and controls. However, examination of KIR in the context of their cognate HLA ligands revealed a strong protective effect for KIR3DL1 in combination with HLA-A and -B alleles bearing the Bw4 motif (P=10(-8); odds ratio (OR)=0.60, confidence interval (CI)=0.50-0.71) and the Bw4 ligand alone (P<10(-6); OR=0.63, CI=0.53-0.75). The observed effect cannot be explained by either a specific HLA-B allele or by linkage disequilibrium with HLA-DRB1 or HLA-A. The protective effect was observed only in individuals who were not positive for the MS risk allele HLA-DRB1*15:01 (P<10(-6); OR=0.61, CI=0.51-0.74). Our study, the first investigation of KIR and MS in African Americans, confirms and refines previous findings in a European cohort.
| S-EPMC5105680 | biostudies-literature
Project description:KIR3DL1 is among the most interesting receptors studied, within the killer immunoglobulin receptor (KIR) family. Human leukocyte antigen (HLA) class I Bw4 epitope inhibits strongly Natural Killer (NK) cell's activity through interaction with KIR3DL1 receptor, while Bw6 generally does not. This interaction has been indicated to play an important role in the immune control of different viral infectious diseases. However, the structural interaction between the KIR3DL1 receptor and different HLA-B alleles has been scarcely studied. To understand the complexity of KIR3DL1-HLA-B interaction, HLA-B alleles carrying Bw4/Bw6 epitope and KIR3DL1?001 allele in presence of different peptides has been evaluated by using a structural immunoinformatic approach. Different energy minimization force fields (ff) have been tested and NOVA ff enables the successful prediction of ligand-receptor interaction. HLA-B alleles carrying Bw4 epitope present the highest capability of interaction with KIR3DL1?001 compared to the HLA-B alleles presenting Bw6. The presence of the epitope Bw4 determines a conformational change which leads to a stronger interaction between nonpolymorphic arginine at position 79 of HLA-B and KIR3DL1?001 136-142 loop. The data shed new light on the modalities of KIR3DL1 interaction with HLA-B alleles essential for the modulation of NK immune-mediated response.
| S-EPMC3747338 | biostudies-literature
Project description:Combinations of KIR3DL1 and HLA-Bw4 alleles protect against HIV infection and/or disease progression. These combinations enhance NK cell responsiveness through the ontological process of education. However, educated KIR3DL1(+) NK cells do not have enhanced degranulation upon direct recognition of autologous HIV-infected cells. Since antibody-dependent cellular cytotoxicity (ADCC) is associated with improved HIV infection outcomes and NK cells overcome inhibition through killer cell immunoglobulin-like receptors (KIR) to mediate ADCC, we hypothesized that KIR3DL1-educated NK cells mediate anti-HIV ADCC against autologous cells. A whole-blood flow cytometry assay was used to evaluate ADCC-induced activation of NK cells. This assay assessed activation (gamma interferon [IFN-?] production and/or CD107a expression) of KIR3DL1(+) and KIR3DL1(-) NK cells, from HLA-Bw4(+) and HLA-Bw4(-) HIV-positive and HIV-negative individuals, in response to autologous HIV-specific ADCC targets. KIR3DL1(+) NK cells were more functional than KIR3DL1(-) NK cells from HLA-Bw4(+), but not HLA-Bw4(-), healthy controls. In HIV-infected individuals, no differences in NK cell functionality were observed between KIR3DL1(+) and KIR3DL1(-) NK cells in HLA-Bw4(+) individuals, consistent with dysfunction of NK cells in the setting of HIV infection. Reflecting the partial normalization of NK cell responsiveness following initiation of antiretroviral therapy, a significant correlation was observed between the peripheral CD4(+) T-lymphocyte counts in antiretroviral therapy-treated subjects and the functionality of NK cells. However, peripheral CD4(+) T-lymphocyte counts were not correlated with an anti-HIV ADCC functional advantage in educated KIR3DL1(+) NK cells. The abrogation of the functional advantage of educated NK cells may enhance HIV disease progression. Strategies to enhance the potency of NK cell-mediated ADCC may improve HIV therapies and vaccines.
| S-EPMC3318670 | biostudies-literature
Project description:KIR3DL1 is a polymorphic inhibitory receptor that modulates NK cell activity through interacting with HLA-A and HLA-B alleles that carry the Bw4 epitope. Amino acid polymorphisms throughout KIR3DL1 impact receptor surface expression and affinity for HLA. KIR3DL1/S1 encodes inhibitory and activating alleles, but despite high homology with KIR3DL1, the activating receptor KIR3DS1 does not bind the same ligand. Allele KIR3DL1*009 resulted from a gene recombination event between the inhibitory receptor allele KIR3DL1*001 and the activating receptor allele KIR3DS1*013. This study analyzed the functional impact of KIR3DS1-specific polymorphisms on KIR3DL1*009 surface expression, binding to HLA, and functional capacity. Flow-cytometric analysis of primary human NK cells as well as transfected HEK293T cells shows that KIR3DL1*009 is expressed at a significantly lower surface density compared with KIR3DL1*001. Using recombinant proteins of KIR3DL1*001, KIR3DL1*009, and KIR3DS1*013 to analyze binding to HLA, we found that although KIR3DL1*009 displayed some evidence of binding to HLA compared with KIR3DS1*013, the binding was minimal compared with KIR3DL1*001 and KIR3DL1*005. Mutagenesis of polymorphic sites revealed that the surface phenotype and reduced binding of KIR3DL1*009 are caused by the combined amino acid polymorphisms at positions 58 and 92 within the D0 extracellular domain. Resulting from these effects, KIR3DL1*009(+) NK cells exhibited significantly less inhibition by HLA-Bw4(+) target cells compared with KIR3DL1*001(+) NK cells. The data from this study contribute novel insight into how KIR3DS1-specific polymorphisms in the extracellular region impact KIR3DL1 surface expression, ligand binding, and inhibitory function.
| S-EPMC4506867 | biostudies-literature
Project description:The major histocompatibility complex (MHC, called HLA in humans) is an important genetic component of the immune system. Fish, birds and mammals prefer mates with different genetic MHC code compared to their own, which they determine using olfactory cues. This preference increases the chances of high MHC variety in the offspring, leading to enhanced resilience against a variety of pathogens. Humans are also able to discriminate HLA related olfactory stimuli, however, it is debated whether this mechanism is of behavioural relevance. We show on a large sample (N = 508), with high-resolution typing of HLA class I/II, that HLA dissimilarity correlates with partnership, sexuality and enhances the desire to procreate. We conclude that HLA mediates mate behaviour in humans.
| S-EPMC5006172 | biostudies-literature
Project description:Viral infections can affect the glycosylation pattern of glycoproteins involved in antiviral immunity. Given the importance of protein glycosylation for immune function, we investigated the effect that modulation of the highly conserved HLA class I N-glycan has on KIR:HLA interactions and NK cell function. We focused on HLA-B*57:01 and its interaction with KIR3DL1, which has been shown to play a critical role in determining the progression of a number of human diseases, including human immunodeficiency virus-1 infection. 721.221 cells stably expressing HLA-B*57:01 were treated with a panel of glycosylation enzyme inhibitors, and HLA class I expression and KIR3DL1 binding was quantified. In addition, the functional outcomes of HLA-B*57:01 N-glycan disruption/modulation on KIR3DL1?+ Jurkat reporter cells and primary human KIR3DL1+ NK cells was assessed. Different glycosylation enzyme inhibitors had varying effects on HLA-B*57:01 expression and KIR3DL1-Fc binding. The most remarkable effect was that of tunicamycin, an inhibitor of the first step of N-glycosylation, which resulted in significantly reduced KIR3DL1-Fc binding despite sustained expression of HLA-B*57:01 on 721.221 cells. This effect was paralleled by decreased activation of KIR3DL1?+ Jurkat reporter cells, as well as increased degranulation of primary human KIR3DL1+ NK cell clones when encountering HLA-B*57:01-expressing 721.221 cells that were pre-treated with tunicamycin. Overall, these results demonstrate that N-glycosylation of HLA class I is important for KIR:HLA binding and has an impact on NK cell function.
| S-EPMC4683028 | biostudies-literature