REGULATION OF HIV-1 CORECEPTORS

HIV-1 辅助受体的调节

• 批准号: 6019921
• 负责人: HARIBABU BODDULURI
• 金额: $ 4.03万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6019921
• 关键词: HIV infections; Italy; cell line; chemokine; cytokine receptors; helper T lymphocyte; human immunodeficiency virus 1; mitogen activated protein kinase; phospholipase A2; receptor expression; receptor sensitivity; virus infection mechanism; virus receptors

The chemokines are a family of structurally related peptides that interact through cell surface G-protein coupled receptors in leukocytes to mediate diverse biological and biochemical activities such as adhesion, directed migration and activation. They play a major role in the pathophysiology of many inflammatory disorders. Chemokine receptors CCR5 or CXCR4 were identified as essential co-receptors for the entry of human immunodeficiency virus HIV-1 into CD4 positive cells. While CCR5 is the target for the entry of primary viruses CXCR4 may be important in the progression to AIDS from asymptomatic infection. The overall objective of the parent proposal is to delineate the pathways of CXCR4 signaling, desensitization and internalization using the RBL-2H3 cells stably co-expressing epitope-tagged native or mutated CXCR4 along with human CD4. In this AIDS-FIRCA, Dr. Sozzani proposes to utilize many reagents (epitope-tagged, green fluorescent protein tagged native and mutated CXCR4 DNAs and transfected RBL cell lines) developed for the parent proposal to determine the role of MAPKs on cPLA2 activation by the ligand SDF-1 and the relevance of this pathway to leukocyte chemotaxis using both pharmacological and biochemical approach. The ability of the HIV-1 envelope glycoproteins (gp120) to induce second messenger formation in CXCR4-expressing RBL-2H3 will be investigated. Activation of MAPKs, and cPLA2 will be evaluated and correlated with the ability of gp120 proteins to induce cell migration. The parent laboratory is utilizing and HIV-1 infection permissive human astroglioma cell line, U87, transfected with human CD4 and native or mutated CXCR4 to determine the role of the signaling evens and internalization in HiV-1 infection. The studies on cPLA2 and MAPKs in RBLs will provide a basis for extension of the same to human cell lines in the parent laboratory and to determine the role of these pathways in HIV-1 infection.

趋化因子是一个结构相关的肽家族， 通过白细胞中的细胞表面 G 蛋白偶联受体相互作用 介导多种生物和生化活动，例如粘附、 定向迁移和激活。他们在其中发挥着重要作用 许多炎症性疾病的病理生理学。趋化因子受体 CCR5 或 CXCR4被确定为人类进入的重要辅助受体 免疫缺陷病毒HIV-1转化为CD4阳性细胞。虽然 CCR5 是目标 对于原发病毒的进入，CXCR4 可能在病毒进展过程中发挥重要作用。 艾滋病源于无症状感染者。父提案的总体目标 是为了描绘 CXCR4 信号传导、脱敏和 使用稳定共表达表位标记的 RBL-2H3 细胞进行内化 天然或突变的 CXCR4 以及人类 CD4。 在本次 AIDS-FIRCA 中，Sozzani 博士建议使用多种试剂 （表位标记、绿色荧光蛋白标记的天然和突变 CXCR4 DNA 和转染的 RBL 细胞系）为母提案开发以确定 MAPKs 对配体 SDF-1 激活 cPLA2 的作用以及相关性 该途径利用药理学和生化手段实现白细胞趋化 方法。 HIV-1 包膜糖蛋白 (gp120) 诱导的能力 将研究表达 CXCR4 的 RBL-2H3 中第二信使的形成。 MAPK 和 cPLA2 的激活将被评估并与 gp120 蛋白诱导细胞迁移的能力。母实验室是 利用HIV-1感染许可的人星形胶质瘤细胞系U87， 用人 CD4 和天然或突变的 CXCR4 转染以确定 HIV-1 感染中的信号传导事件和内化。有关的研究 RBL 中的 cPLA2 和 MAPK 将为将其扩展到人类提供基础 母实验室的细胞系并确定这些途径的作用 HIV-1 感染。