Effects of genetic polymorphism in MHC, KIR, and related loci on human disease

MHC、KIR及相关位点遗传多态性对人类疾病的影响

• 批准号: 10014444
• 负责人: Mary N. Carrington
• 金额: $ 134.58万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10014444
• 关键词: 3' Untranslated Regions; Advanced Malignant Neoplasm; Affect; Alleles; Antigenic Variation; Autoimmune Diseases; Automobile Driving; Binding; Binding Sites; Biological; Biological Process; Blood group antigen f; CCR5 gene; CD4 Positive T Lymphocytes; CTLA4 gene; Cancer Patient; Cell surface; Cells; Characteristics; Chromosomes, Human, Pair 3; Clinical; Communicable Diseases; Complex; DNA; Data; Data Set; Databases; Disease; Disease Outcome; Disease Progression; Down-Regulation; Drug Targeting; Gene Cluster; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; HIV; HIV Infections; HIV Receptors; HIV-1; HLA Antigens; Histocompatibility Antigens Class I; Human Characteristics; Human Chromosomes; Immune; Immune Evasion; Immune Response Genes; Immune checkpoint inhibitor; Immune response; Immunogenetics; Immunoglobulins; Immunologic Receptors; Immunotherapy; In Vitro; Individual; Infection; Inflammatory; Innate Immune Response; Killer Cells; Knowledge; Laboratories; Leukocytes; Ligands; Malignant Neoplasms; Mediating; Medical Genetics; Messenger RNA; Minority; Molecular; Non-Small-Cell Lung Carcinoma; Outcome; PDCD1LG1 gene; Patients; Peptides; Plasma; Positioning Attribute; Predisposition; Property; RNA-Binding Proteins; Research; Resistance; Resources; SLEB2 gene; Signal Pathway; Specificity; Surface; T-Lymphocyte; Testing; Transmembrane Domain; Transplantation; United States National Institutes of Health; Untranslated RNA; Variant; Viral; Viral Proteins; Viral reservoir; Virus; Virus Diseases; Work; activating transcription factor 1; adaptive immune response; antiretroviral therapy; cancer cell; cancer type; cell type; checkpoint therapy; chemokine receptor; chronic infection; cohort; differential expression; genetic association; genome-wide; human disease; immune checkpoint blockade; interest; knock-down; melanoma; mutant; novel; peptide I; preservation; pressure; receptor; response; tool; vpu Protein

We have begun to test for associations between HLA variation and publicly available data on responses to immune checkpoint inhibitors (ICI) across a number of cancer types. It was recently demonstrated that homozygosity at HLA class I associates with poor response to checkpoint blockade immunotherapy, which parallels our earlier findings on a deleterious effect of homozygosity on HIV disease progression. Homozygosity theoretically limits the peptide repertoire presented to CTL, resulting in overall weaker immune responses compared to that in people with more diverse class I genotypes. We have used publicly available data from a previous study, which includes 1535 advanced cancer patients treated with drugs targeting CTLA4 and or PD1, PDL1, in order to investigate more thoroughly the influence of HLA class I variation on immunotherapy. We observed an association between HLA A03 and poor response to checkpoint blockade immunotherapy among combined cancer cell types, and HLA A0301 homozygosity has a stronger effect than homozygosity for any other HLA A allele. The effect was more pronounced if patients with melanoma and non-small cell lung cancer were excluded, suggesting that HLA effects are likely to be cancer type specific to some extent. We will attempt to validate these findings in an independent cohort and determine which cancers are driving the effect. This line of research, which we intend to continue more rigorously, could help predict which patients are more or less likely to respond to checkpoint blockade immunotherapy. We have begun to work with clinicians in the NIH Clinical Center to gain access to materials in their trials of ICI therapy so that we can study these effects in much greater detail. We will have access to DNA from the NCI trials along with matched clinical and genetic data, the likes of which are not available in public databases. HIV1 can downregulate HLA C on infected cells, using the viral protein Vpu, and the magnitude of this downregulation varies widely between primary HIV1 variants. The selection pressures that result in viral downregulation of HLA C in some individuals, but preservation of surface HLA C in others are not clear. To better understand viral immune evasion targeting HLA C, we have characterized HLA C downregulation by a range of primary HIV1 viruses. 128 replication competent viral isolates from 19 individuals with effective anti-retroviral therapy, show that a substantial minority of individuals harbor latent reservoir virus which strongly downregulates HLA C. Untreated infections display no change in HLA C downregulation during the first 6 months of infection, but variation between viral quasispecies can be detected in chronic infection. Vpu molecules cloned from plasma of 195 treatment naive individuals in chronic infection demonstrate that downregulation of HLA C adapts to host HLA genotype. HLA C alleles differ in the pressure they exert for downregulation, and individuals with higher levels of HLA C expression favor greater viral downregulation of HLA C. Studies of primary and mutant molecules identify 5 residues in the transmembrane region of Vpu, and 4 residues in the transmembrane domain of HLA C, which determine interactions between Vpu and HLA. The observed adaptation of Vpu-mediated downregulation to host genotype indicates that HLA C alleles differ in likelihood of mediating a CTL response that is subverted by viral downregulation, and that preservation of HLA C expression is favored in the absence of these responses. Finding that latent reservoir viruses can downregulate HLA C could have implications for HIV1 cure therapy approaches in some individuals. The chemokine receptor gene cluster on human chromosome 3 encodes the primary co-receptor for HIV, CCR5. Multiple genomewide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV coreceptor CCR5, but the functional basis for the strongest of these associations, rs1015164AG, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4 T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3'untranslated region, protecting CCR5 messenger RNA from Raly mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4 T cells with CCR5 tropic HIV in vitro. These data represent a rare determination of the functional importance of a genomewide disease association where expression of a lncRNA affects HIV infection and disease progression.

我们已经开始在多种癌症类型中测试人类白细胞抗原的变异与免疫检查点抑制剂(ICI)反应的公开数据之间的关联。最近的研究表明，HLAI类基因的纯合性与检查点阻断免疫疗法的不良反应有关，这与我们早期关于纯合子对HIV疾病进展的有害影响的研究结果是一致的。纯合性理论上限制了呈递给CTL的多肽库，导致与具有更多I类基因多样性的人相比，总体免疫反应较弱。我们使用了先前一项研究的公开数据，该研究包括1535名接受针对CTLA4和/或PD1、PDL1的药物治疗的晚期癌症患者，以更彻底地调查人类白细胞抗原I类变异对免疫治疗的影响。我们观察到，在联合癌细胞类型中，HLAA03与检查点阻断免疫治疗反应差之间存在关联，对于任何其他HLAA等位基因，HLAA0301纯合子的影响强于任何其他HLAA等位基因。如果排除黑色素瘤和非小细胞肺癌患者，这种影响更加明显，这表明人类白细胞抗原的影响在某种程度上可能是癌症类型特有的。我们将尝试在一个独立的队列中验证这些发现，并确定哪些癌症推动了这一效果。我们打算更严格地继续这一系列研究，这可能有助于预测哪些患者对检查点阻断免疫疗法有或多或少的反应。我们已经开始与NIH临床中心的临床医生合作，在他们的ICI治疗试验中获得材料，以便我们可以更详细地研究这些影响。我们将获得NCI试验的DNA以及匹配的临床和基因数据，这些数据在公共数据库中是无法获得的。HIV1可以利用病毒蛋白VPU下调感染细胞上的HLAC，而且这种下调的幅度在HIV1的主要变种之间差别很大。在一些个体中，选择压力导致病毒下调了HLAC，但在另一些个体中，表面HLAC的保存尚不清楚。为了更好地了解针对人类白细胞抗原C的病毒免疫逃避，我们研究了一系列主要的HIV1病毒对人类白细胞抗原C的下调。来自19个接受有效抗逆转录病毒治疗的个体的128个具有复制能力的病毒分离株显示，相当少数的个体携带有强烈下调HLAC的潜伏库病毒。未经治疗的感染在感染的前6个月没有表现出HLAC下调的变化，但在慢性感染中可以检测到病毒准种之间的变异。从195例慢性感染初治患者的血浆中克隆的VPU分子表明，HLAC的下调与宿主的HLA型相适应。人类白细胞抗原C等位基因的下调压力不同，人类白细胞抗原C表达水平较高的个体更倾向于病毒对人类白细胞抗原C的下调。原始分子和突变分子的研究确定了VPU跨膜区的5个残基和HLAC跨膜区的4个残基，这些残基决定了VPU和HLA之间的相互作用。观察到VPU介导的下调对宿主基因型的适应表明，人类白细胞抗原C等位基因在介导被病毒下调所破坏的CTL反应的可能性上有所不同，在缺乏这些反应的情况下，有利于保存人类白细胞抗原C的表达。发现潜伏的水库病毒可以下调HLAC，这可能对某些人的HIV1治疗方法有意义。人类3号染色体上的趋化因子受体基因簇编码HIV的主要辅助受体CCR5。多项全基因组研究已经确定了人类免疫缺陷病毒(HIV)感染的结局与编码HIV辅助受体CCR5的基因及其周围的多态之间的关联，但这些关联中最强的rs1015164AG的功能基础尚不清楚。我们发现rs1015164标记了激活转录因子1结合位点的变异，该结合位点控制反义长非编码RNA(LncRNA)CCR5AS的表达。CCR5AS表达下调或增强可导致CD4T细胞CCR5表达相应改变。CCR5AS干扰RNA结合蛋白Raly和CCR5 3‘非翻译区之间的相互作用，保护CCR5信使RNA不受Raly介导的降解。通过抑制CCR5减少CCR5的表达可减少CD4T细胞对CCR5嗜性HIV的体外感染。这些数据罕见地确定了全基因组疾病关联的功能重要性，在这种关联中，lncRNA的表达影响艾滋病毒感染和疾病进展。