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 | $799,639 | Project Dates | 10/01/2006 - 00/00/0000 |
Fiscal Year | 2014 | 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%) Digestive Diseases (10.0%) |
Cervical Cancer (10.0%) Head and Neck (30.0%) Kaposi Sarcoma (20.0%) Leukemia (15.0%) Liver Cancer (10.0%) Sarcoma (15.0%) |
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Research Type | |||
Cancer Progression and Metastasis Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
The HLA class I genes are the most polymorphic loci in the human genome, resulting in the ability of the system to bind and present a great variety of antigenic peptides to cytotoxic T lymphocytes. HLA-C molecules are expressed at a low level on the cell surface compared with HLA-A and -B. Unlike HLA-A and -B, HLA-C surface expression is not down-regulated by Nef upon HIV infection. We previously demonstrated that HLA-C allotypes are expressed at variable levels on the cell surface in a manner that is allotype-specific, and higher surface expression mediates greater selection pressure on HIV-1 and better viral control overall. We further showed that polymorphism in the miR-148a binding site in the HLA-C 3prime untranslated region (3 prime UTR) region partially explains differential expression of the various HLA-C allotypes, where miR-148a inhibits expression of HLA-C alleles that have an intact binding site but does not affect expression of escape HLA-C alleles that contain a disrupted binding site, which is not recognized by miR-148a. In general, the escape alleles are expressed at a higher level than the inhibited alleles (although there are exceptions). We have now demonstrated that the expression levels of miR-148a, as marked by MIR148A gene variation, correlate positively with HIV viral load among those individuals who carry at least one inhibited HLA-C allele. There is no correlation between the level of miR-148a and HIV control among those individuals who carry two copies of HLA-C escape alleles. Alternatively, the genotype marking higher miR-148a expression levels (which lead to lower HLA-C expression) results in protection against Crohn's disease (CD) among those who carry at least one inhibited HLA-C allele. These data underscore the importance of immune gene interactions in human disease and the independent role of HLA-C expression levels in HIV viral control and risk of CD. Natural progression of HIV-1 infection depends on genetic variation in the human 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 HIV-1 by changing interactions of 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 previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Analyses in persons of European descent, the largest ethnic group examined, showed 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 associated 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. In vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs, suggesting an impact of LILRB2 on HIV-1 immune control through altered regulation of DCs by LILRB2-HLA engagement. HLA-disease associations have been shown in some cases to link to the peptide-binding characteristics of individual HLA class I molecules. In collaboration with Dr. Malini Raghavan at the University of Michigan, we showed that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide-deficient forms. In particular, dependence on the" |