ZIA BC 010791 (ZIA) | |||
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Title | Effects of genetic polymorphism in MHC, KIR, and related loci on human disease | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Carrington, Mary | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $820,830 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (10.0%) Bone Marrow Transplantation (10.0%) Cancer (100.0%) |
Cervical Cancer (15.0%) Head and Neck (30.0%) Leukemia (20.0%) Lung (10.0%) |
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Research Type | |||
Cancer Progression & Metastasis Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
HLA-A expression levels and HIV. We previously demonstrated that HLA-A expression levels vary in an allele dependent manner and showed that DNA methylation of the HLA-A gene appears to contribute to the variation in HLA-A mRNA expression levels. Usage of alternative polyadenylation signals in the HLA-A 3'UTR, which was also allele dependent, was found to associate posttranscriptionally with cell surface expression levels and represents a second factor that explains differential expression levels of HLA-A allotypes. Analysis of 9,763 HIV infected subjects from 21 cohorts shows that higher HLA-A levels confer poorer control of HIV, an observation that was consistent across clinical outcomes and populations. Elevated HLA-A expression provides enhanced levels of an HLA-A derived signal peptide that specifically binds and determines expression levels of HLA-E, the ligand for the inhibitory NKG2A Natural Killer (NK) cell receptor. HLA-B haplotypes that favor NKG2A-mediated NK cell licensing/education exacerbate the deleterious effect of high HLA-A on HIV control, consistent with NKG2A-mediated inhibition impairing NK cell clearance of HIV-infected targets. We determined the functional basis for this observation: higher HLA-A expression results in higher expression of HLA-E, the ligand for the strongly inhibitory receptor, NKG2A. Our functional studies support the model that NK cell inhibition through NKG2A recognition of HLA-E results in poor effector cell responses to HIV infected cells and strongly point to HLA-E-NKG2A mediated inhibition of effector cells as a primary susceptibility factor in HIV pathogenesis. KIR3DL1 genotype modifies HLA-B*57 protection in HIV disease. The most consistent host factor associated with control of HIV is HLA-B*57, which is highly enriched among HIV infected individuals who are able to maintain undetectable viral loads in the absence of antiretroviral therapy, referred to as elite controllers. Nevertheless, there is extensive heterogeneity in level of HIV control among B*57+ individuals, where many B*57 positive subjects progress as rapidly to AIDS as those who do not carry B*57. We performed whole genome sequencing to identify variants that may modify control of HIV among B*57+ subjects. A single common variant that encodes an isoleucine to valine substitution at position 47 (I47V) of the inhibitory NK cell receptor KIR3DL1 was the only genome wide significant modifier of B*57 protection, where 47V conferred protection. The association was conclusively verified in a second cohort of viremic controllers compared to non-controllers (p = 4 x 10-3), and in a third analysis of longitudinal viral load and CD4 T cell counts (p = 4.9 x 10-18 and 1.5 x 10-6, respectively). The modifying effect of I47V was confined to B*57:01 and was not observed for the closely related B*57:03. The data indicate that fine specificity of interaction between KIR3DL1 allotypes and their HLA-B ligands likely affects the NK cell response to HIV-infected cells. HLA gene diversity reduces risk for non-Hodgkin lymphoma (NHL). HLA class I molecules present foreign antigens primarily to cytotoxic T-cells that in response kill these target cells, while HLA class II molecules stimulate antibody production in response to specific antigens. Reduced diversity, as defined by homozygosity at each co-dominant HLA loci, might adversely affect the host's ability to recognize a more diverse array of foreign antigens and thereby increase subsequent disease burden. This concept is supported by a priori research that has examined effects of HLA zygosity on infectious disease, whereby a lack of HLA class I and II diversity has been associated with increased risk of HIV and hepatitis B virus infection. Given the growing evidence that genetic variation within HLA genes play in the etiology of NHL subtypes, we specifically aimed to test whether lack of HLA diversity as measured by HLA homozygosity, was associated with increased NHL risk. We used a poo |