SDF-1 3' UTR MUTATION DELAYS PROGRESSION TO AIDS

SDF-1 3 UTR 突变延迟进展为艾滋病

• 批准号: 6289333
• 负责人: CHERYL ANN WINKLER
• 金额: --
• 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/6289333
• 关键词: AIDS; cytokine receptors; disease /disorder proneness /risk; gene mutation; genetic polymorphism; human immunodeficiency virus 1; human tissue; immunogenetics; pathologic process; receptor binding; virus infection mechanism; virus receptors

SDF1-3?A is a mutation in an evolutionarily conserved region of the 3?UTR. Our working hypothesis has been that the SDF1-3?A mutation stabilizes the mRNA and thus increases the amount of transcript available for translation. This may result in an increase of SDF-1 available for binding to CXCR4 and a downregulation of surface CXCR4 expression. Careful sequencing of the 5?UTR and the open reading frame have not revealed any other polymorphisms in linkage disequilibrium with SDF1-3?A or associated with rate of disease progression. In collaborative studies, a sensitive assay for determining serum SDF-1 concentrations is being used to quantify serum SDF-1 concentrations in normal donors with the three SDF-1 genotypes. We are also examining the expression of SDF1 by quantifying mRNA SDF1 in stromal cells derived from a normal population. A full length SDF1-3?UTR construct of the wild type and SDF1-3?A UTR differing by a single nucleotide have differential abilities to stabilize mRNA when ligated to a reporter gene. Finally,we are examining the surface expression of CXCR4 using fluorescence activated flow sorting analysis quantification of peripheral blood mononuclear cells from normal donors of the three genotypes. Very preliminary data show a trend of less surface CXCR4 on cells obtained from donors of the SDF1-3?A/SDF1-3?A genotypes compared to individuals carrying the wildtype allele. These experiments are being expanded to include additional SDF1-3?A/SDF1-3?A genotypes which have been identified from a pool of normal donors. Paradoxically, SDF1- 3?A, which appears to recessively protect individuals from developing AIDS in the first decade after infection in our cohorts, has been associated with an increased dominant risk for developing non-Hodgkins lymphoma in a study of HIV-1-infected hemophiliacs and homosexuals, and infants infected by vertical transmission. We have performed a categorical analysis comparing allele and genotype frequencies between HIV seropositive cases with non-Hodgkins lymphoma and controls matched for duration of HIV-1 infection and CD4 T-cell number and have been unable to detect significant differences in allele or genotype frequencies between cases and controls. We have entered into a collaboration to perform survival analyses using Multicenter AIDS Cohort Study seroconverter participants to confirm or refute this clinically important observation. The SDF1 Gene and Progression to AIDS - Chemokines, SDF-1, HIV-1 inhibitor, lymphoma, - Human Tissues, Fluids, Cells, etc.

SDF1-3？A是位于3？非编码区进化保守区域的突变。我们的工作假设是，SDF1-3α突变稳定了mRNA，从而增加了可供翻译的转录本的数量。这可能导致可与CXCR4结合的SDF-1增加，并下调表面CXCR4的表达。对5？非编码区和开放阅读框的仔细测序没有发现与SDF1-3？A连锁不平衡或与疾病进展速度相关的任何其他多态。在合作研究中，一种测定血清SDF-1浓度的灵敏方法正被用于定量具有三种SDF-1基因的正常献血者的血清SDF-1浓度。我们还通过定量检测来自正常人群的基质细胞中SDF1的mRNA来检测SDF1的表达。野生型的全长SDF1-3非编码区和单核苷酸不同的SDF1-3非编码区在连接到报告基因时具有不同的稳定mRNA的能力。最后，我们用荧光活化流动分选分析定量检测了三种基因型的正常献血者外周血单个核细胞表面CXCR4的表达。非常初步的数据显示，与携带野生型等位基因的个体相比，来自SDF1-3？A/SDF1-3？A基因携带者的细胞表面CXCR4有减少的趋势。这些实验正在扩大，以包括从正常献血者库中鉴定出的其他SDF1-3？A/SDF1-3？A基因型。矛盾的是，在我们的队列中感染后的第一个十年里，SDF1-3？A似乎在隐性地保护个人免受艾滋病的侵袭，但在一项针对感染HIV-1的血友病患者和同性恋者以及通过垂直传播感染的婴儿的研究中，SDF1-3？A与患非霍奇金淋巴瘤的主要风险增加有关。我们进行了一项分类分析，比较了HIV血清阳性的非霍奇金淋巴瘤患者和与HIV-1感染持续时间和CD4T细胞数量匹配的对照组的等位基因和基因型频率，但未能检测到病例和对照组之间的等位基因或基因型频率的显著差异。我们进行了一项合作，利用多中心艾滋病队列研究血清转换参与者进行生存分析，以证实或驳斥这一临床上重要的观察结果。SDF1基因与艾滋病的进展--趋化因子、SDF-1、HIV-1抑制物、淋巴瘤、人体组织、体液、细胞等。