CONTROL OF HIV AND INDUCIBLE T CELL GENE PRODUCTS

HIV 和诱导性 T 细胞基因产物的控制

• 批准号: 3454850
• 负责人: Gary J Nabel
• 金额: $ 11.13万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-01 至 1993-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3454850
• 关键词: Adenoviridae; DNA binding protein; HIV infections; Herpesviridae; Papovaviridae; T lymphocyte; cyclosporines; gene expression; gene induction /repression; genetic enhancer element; genetic manipulation; genetic promoter element; glucocorticoids; human T cell lymphotropic virus type 1; human immunodeficiency virus 2; interferons; interleukin 2; interleukin 3; interleukin 4; leukocyte activation /transformation; lymphokines; oligonucleotides; plasmids; synthetic nucleotide; transcription factor; virus genetics

Activation of T cells leads to the synthesis of set of coordinately expressed gene products, including several lymphokines. The expression of human immunodeficiency virus (HIV) also increases following activation of T cells containing this virus. We have shown that a transcription factor, NF-kB, becomes activated in T cells to cause this induction. A major goal of this proposal is to understand how DNA binding proteins regulate the expression of HIV in T cells and to identify agents which might modulate HIV expression without affecting inducible lymphokines, particularly interleukin (IL)-2. The proteins which bind to regulatory regions of these inducible genes will be identified and the functional role of their binding sites assessed by mutational analysis. The relevant proteins and their respective binding sites will be compared to those in y-interferon (y-IFN), IL-3, and IL-4 to identify common transcription factors and sites which may coordinately regulate these genes. A DNA binding protein which negatively regulates the expression of IL-2 has been found whose binding site is present also in a regulatory region of y-IFN and IL-4. The regulation of this DNA binding protein in comparison to NF-kB will be analyzed. The mechanism of activation for HIV will also be explored further using viral transactivator genes from herpesvirus, adenovirus, papovavirus, or HTLV-I. The expression of HIV enhancer mutants with altered sites in the HIV promoter and enhancer will be tested using the herpesvirus ICPO, adenovirus E1A, papovavirus E2, or HTLV-I tat transactivators. Changes in binding of NF-kB, other HIV regulatory proteins, or 2 DNA binding proteins will also be determined in response to treatment with different physiologic or pharmacologic activators. Finally, agents which might prevent the binding and action of these transcription factors, such as glucocorticoids, cyclosporin A or synthetic oligonucleotide analogues will be examined. Understanding the molecular basis of this coordinate gene expression will help to develop strategies to prevent the expression of HIV selectively in T cells.

T 细胞的激活导致一组协调的合成 表达的基因产物，包括几种淋巴因子。 这 人类免疫缺陷病毒（HIV）的表达也增加 含有该病毒的 T 细胞被激活后。 我们有 表明转录因子 NF-kB 在 T 中被激活 细胞引起这种诱导。 该提案的一个主要目标是 了解 DNA 结合蛋白如何调节 T 细胞中的 HIV 并鉴定可能调节 HIV 的药物 表达不影响诱导性淋巴因子，特别是 白细胞介素（IL）-2。 与调节区域结合的蛋白质 这些诱导基因的一部分将被鉴定，并且其功能作用 通过突变分析评估其结合位点。 这 相关蛋白质及其各自的结合位点将是 与 y-干扰素 (y-IFN)、IL-3 和 IL-4 相比 识别常见的转录因子和位点 协调调节这些基因。 一种 DNA 结合蛋白， 负调控IL-2的表达已被发现 结合位点也存在于 y-IFN 的调节区域中 IL-4。 该 DNA 结合蛋白的调节与 将分析 NF-kB。 HIV的激活机制将 还可以使用来自的病毒反式激活基因进行进一步探索 疱疹病毒、腺病毒、乳多空病毒或 HTLV-I。 表达式 HIV启动子中具有改变位点的HIV增强子突变体和 增强子将使用疱疹病毒 ICPO、腺病毒 E1A、 乳多空病毒 E2 或 HTLV-I tat 反式激活剂。 绑定的变化 NF-kB、其他 HIV 调节蛋白或 2 个 DNA 结合蛋白 也将根据不同治疗的反应来确定 生理或药理激活剂。 最后，代理商 可能会阻止这些转录的结合和作用 因素，如糖皮质激素、环孢菌素 A 或合成药物 将检查寡核苷酸类似物。 了解 这种协调基因表达的分子基础将有助于 制定战略以选择性地预防艾滋病毒的表达 T细胞。