SDF-1 3' UTR MUTATION DELAYS PROGRESSION TO AIDS

SDF 1 -3？A是在进化上保守的3？UTR。我们的工作假设是SDF 1 -3？突变使mRNA稳定，从而增加可用于翻译的转录物的量。这可能导致可用于结合CXCR 4的SDF-1的增加和表面CXCR 4表达的下调。仔细排列5个？UTR和开放阅读框架没有发现任何其他多态性与SDF 1 -3连锁不平衡？A或与疾病进展率相关。在合作研究中，用于测定血清SDF-1浓度的灵敏测定法被用于定量具有三种SDF-1基因型的正常供体的血清SDF-1浓度。我们还通过定量来自正常人群的基质细胞中SDF 1的mRNA来检测SDF 1的表达。全长SDF 1 -3？野生型和SDF 1 -3？当与报告基因连接时，相差单个核苷酸的UTR具有不同的稳定mRNA的能力。 最后，我们使用荧光激活流式分选分析法对来自三种基因型的正常供体的外周血单个核细胞的CXCR 4的表面表达进行了检测。非常初步的数据显示，从SDF 1 -3？A/SDF 1 -3？A基因型与携带野生型等位基因的个体相比。这些实验正在扩展到包括额外的SDF 1 -3？A/SDF 1 -3？从正常供体库中鉴定的基因型。特别是SDF 1 - 3？在我们的队列中，A似乎在感染后的第一个十年内保护个体免于发展为艾滋病，在一项对HIV-1感染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，A与发展为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-1感染持续时间和CD 4 T细胞数量匹配的HIV血清阳性非霍奇金淋巴瘤病例和对照组之间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等位基因或基因型频率的显著差异。我们已经开始合作，使用多中心艾滋病队列研究血清转换者参与者进行生存分析，以证实或反驳这一临床重要观察结果。SDF 1基因与艾滋病的进展-趋化因子，SDF-1，HIV-1抑制剂，淋巴瘤，-人体组织，液体，细胞等。

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.