Immunogenetics of HIV disease Martin, Maureen P.; Carrington, Mary
Immunological reviews,
July 2013, Volume:
254, Issue:
1
Journal Article
Peer reviewed
Open access
Summary
Host genetic factors are a major contributing factor to the inter‐individual variation observed in response to human immunodeficiency virus (HIV) infection and are linked to resistance to HIV ...infection among exposed individuals, as well as rate of disease progression and the likelihood of viral transmission. Of the genetic variants that have been shown to affect the natural history of HIV infection, the human leukocyte antigen (HLA) class I genes exhibit the strongest and most consistent association, underscoring a central role for CD8+ T cells in resistance to the virus. HLA proteins play important roles in T‐cell‐mediated adaptive immunity by presenting immunodominant HIV epitopes to cytotoxic T lymphocytes (CTLs) and CD4+ T cells. Genetic and functional data also indicate a function for HLA in natural killer cell‐mediated innate immunity against HIV by interacting with killer cell immunoglobulin‐like receptors (KIR). We review the HLA and KIR associations with HIV disease and discuss the mechanisms underlying these associations.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
High HLA-DP Expression and Graft-versus-Host Disease Petersdorf, Effie W; Malkki, Mari; O’hUigin, Colm ...
New England journal of medicine/The New England journal of medicine,
08/2015, Volume:
373, Issue:
7
Journal Article
Peer reviewed
Open access
When the donor and recipient are mismatched at HLA-DPB1, the risk of graft-versus-host disease is high. The authors found that when the donor has a particular regulatory allele that lowers expression ...of HLA-DPB1, the risk of GVHD is lower.
Hematopoietic-cell transplantation from unrelated donors can cure blood disorders; however, graft-versus-host disease (GVHD) remains a major impediment to successful outcomes.
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GVHD can occur after HLA-matched transplantation when the donor cells recognize polymorphic peptides (“minor histocompatibility antigens”) presented by the recipient’s HLA.
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In HLA-mismatched transplantation, direct recognition of the recipient’s mismatched HLA by the donor’s cells provides a potent stimulus for graft-versus-host allorecognition
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; recognition of the donor’s mismatched HLA by the recipient’s immune system leads to graft rejection.
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The importance of HLA class II alloantigens was established early in the history of clinical transplantation.
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Advances in understanding the . . .
Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human ...leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individual's HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.
Abstract Killer cell immunoglobulin-like receptors ( KIR ) are expressed on natural killer (NK) cells and subsets of T cells. The KIR genes are polymorphic and the KIR gene complex is polygenic with ...varying numbers of inhibitory and activating receptors. HLA class I molecules serve as ligands for the KIR. Interactions of the independently segregating KIR and HLA loci are important for recognition of targets by NK cells as well as NK cell ‘licensing’. Several disease association studies indicate a role for interactions between these loci in infectious diseases, autoimmune/inflammatory disorders, cancer and reproduction. Emerging functional data supports a mechanism based on a continuum of inhibition to activation through various compound KIR – HLA genotypes in diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The expression level of HLA class-I proteins is known to influence pathological outcomes: pathogens downregulate HLA to evade host immune responses, host inflammatory reactions upregulate HLA, and ...differences among people with regard to the steady-state expression levels of HLA associate with disease susceptibility. Yet precise quantification of relative expression levels of the various HLA loci is difficult because of the tremendous polymorphism of HLA. We report relative expression levels of HLA-A, HLA-B, HLA-C, and HLA-E proteins for the specific haplotype A*02:01, B*44:02, C*05:01, which were characterized using two independent methods based on flow cytometry and mass spectrometry. PBLs from normal donors showed that HLA-A and HLA-B proteins are expressed at similar levels, which are 13-18 times higher than HLA-C by flow cytometry and 4-5 times higher than HLA-C by mass spectrometry; these differences may reflect variation in the conformation or location of proteins detected. HLA-E was detected at a level 25 times lower than that of HLA-C by mass spectrometry. Primary CD4(+) T cells infected with HIV in vitro were also studied because HIV downregulates selective HLA types. HLA-A and HLA-B were reduced on HIV-infected cells by a magnitude that varied between cells in an infected culture. Averaging all infected cells from an individual showed HLA-A to be 1-3 times higher and HLA-B to be 2-5 times higher than HLA-C by flow cytometry. These results quantify substantial differences in expression levels of the proteins from different HLA loci, which are very likely physiologically significant on both uninfected and HIV-infected cells.
The discovery of an unexpected level of diversity among the killer cell immunoglobulin‐like receptors has led to a search for their role in human disease. Due to their polymorphism and also that of ...their human leukocyte antigen class I ligands, these studies are difficult to perform and complex to interpret. Nevertheless, as the number of data sets increase, consistent trends and themes are beginning to emerge in both viral and inflammatory disorders. In this review, we summarize the findings from a number of disease association studies and discuss these in the context of the activating and inhibitory roles of the members of this gene family.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The activating natural killer (NK)-cell receptor KIR3DS1 has been linked to the outcome of various human diseases, including delayed progression of disease caused by human immunodeficiency virus type ...1 (HIV-1), yet a ligand that would account for its biological effects has remained unknown. We screened 100 HLA class I proteins and found that KIR3DS1 bound to HLA-F, a result we confirmed biochemically and functionally. Primary human KIR3DS1(+) NK cells degranulated and produced antiviral cytokines after encountering HLA-F and inhibited HIV-1 replication in vitro. Activation of CD4(+) T cells triggered the transcription and surface expression of HLA-F mRNA and HLA-F protein, respectively, and induced binding of KIR3DS1. HIV-1 infection further increased the transcription of HLA-F mRNA but decreased the binding of KIR3DS1, indicative of a mechanism for evading recognition by KIR3DS1(+) NK cells. Thus, we have established HLA-F as a ligand of KIR3DS1 and have demonstrated cell-context-dependent expression of HLA-F that might explain the widespread influence of KIR3DS1 in human disease.
Host genetic variation is presently estimated to account for about one-fourth of the observed differences in control of HIV across infected individuals. Genome-wide association studies have confirmed ...that polymorphism within the HLA class I locus is the primary host genetic contributor to determining outcome after infection. Here we progress beyond the genetic associations alone to consider the functional explanations for these correlations. In this process, the complex and multidimensional effects of HLA molecules in viral disease become apparent.
The main aim of this study was to evaluate the significance of HLA-DPB1 expression in acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) from HLA-A, -B, -C, -DRB1, ...-DQB1-matched and -mismatched unrelated donors.
Between January 1, 2017, and January 10, 2019, we assessed 19,136 patients who received HCT from an HLA-A, -B, -C, -DRB1, -DQB1-matched or -mismatched unrelated donor performed in Australia, the European Union, Japan, North America, and the United Kingdom between 1988 and 2016. Among transplant recipients with one HLA-DPB1 mismatch, the patient's mismatched HLA-DPB1 allotype was defined as low or high expression. Multivariable regression models were used to assess risks of GVHD associated with high expression relative to low expression HLA-DPB1 mismatches. The effect of increasing numbers of HLA-DPB1 mismatches on clinical outcome was assessed in HLA-mismatched transplant recipients.
In HLA-A, -B, -C, -DRB1,-DQB1-matched transplant recipients, donor mismatching against one high-expression patient HLA-DPB1 increased moderate (odds ratio OR, 1.36;
= .001) and severe acute GVHD (OR, 1.32;
= .0016) relative to low-expression patient mismatches, regardless of the expression level of the donor's mismatched HLA-DPB1. Among transplant recipients with one HLA-A, -B, -C, -DRB1, or -DQB1 mismatch, the odds of acute GVHD increased with increasing numbers of HLA-DPB1 mismatches (OR, 1.23 for one; OR, 1.40 for two mismatches relative to zero mismatches for moderate GVHD; OR, 1.19 for one; OR, 1.40 for two mismatches relative to zero for severe GVHD), but not with the level of expression of the patient's mismatched HLA-DPB1 allotype.
The level of expression of patient HLA-DPB1 mismatches informs the risk of GVHD after HLA-A, -B, -C, -DRB1, -DQB1-matched unrelated HCT, and the total number of HLA-DPB1 mismatches informs the risk of GVHD after HLA-mismatched unrelated HCT. Prospective consideration of HLA-DPB1 may help to lower GVHD risks after transplantation.
Although dominant C₄ grasses in tallgrass prairie are highly mycotrophic, for many non-dominant species neither extent of mycorrhizal colonization nor root morphology effects on plant–soil feedback ...interactions are known. In a laboratory study conducted from November 2013 to February 2014 at Governors State University (University Park, IL), we grew plants of a dominant C₄ grass (Andropogon gerardii) and three non-dominant forbs (Symphyotrichum laeve var. laeve, Symphyotrichum novaeangliae and Parthenium integrifolium) individually in soil collected in the field beneath a conspecific, collected beneath another study species, or in sterilized soil. The study addressed the following questions: (1) Is extent of mycorrhizal colonization of roots related to root structure? (2) How does soil history interact with plant root traits to influence plant–soil feedback? (3) How might plant–soil feedback patterns influence competitive interactions among study species? We found that proportion arbuscular mycorrhizal fungi (AMF) colonization decreased with increasing specific root length. Soil history had a stronger influence than plant species on total biomass of plants, with all species having highest total biomass when grown in Andropogon soil. Consequently, net, or heterospecific, feedback did not differ among pairwise species combinations, and was not different from 0. While these results suggest that no study species should have a competitive advantage in the field, Andropogon might still have an advantage through mechanisms such as competition for light. Future work in the field and including less mycotrophic species is needed to better understand AMF effects on competitive interactions.
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