REGULATION OF HIV-1 CORECEPTORS

趋化因子是结构上相关的肽家族， 通过白细胞中的细胞表面G蛋白偶联受体相互作用， 介导多种生物和生物化学活性， 定向迁移和激活。他们在这方面发挥着重要作用， 许多炎症性疾病的病理生理学。趋化因子受体CCR 5或 CXCR 4被鉴定为人类细胞进入细胞的必需共受体。 免疫缺陷病毒HIV-1进入CD 4阳性细胞。CCR 5是目标 对于原发性病毒的进入，CXCR 4可能在进展中很重要， 艾滋病无症状感染者。母提案的总体目标 是描绘CXCR 4信号传导、脱敏和 使用稳定共表达表位标记的RBL-2 H3细胞的内化 天然或突变的CXCR 4沿着人CD 4。 在这个艾滋病-FIRCA中，Sozzani博士建议使用许多试剂 （表位标记的、绿色荧光蛋白标记的天然和突变的CXCR 4 DNA 和转染的RBL细胞系），以确定 MAPKs在配体SDF-1激活cPLA 2中的作用以及 这一途径的白细胞趋化性使用药理学和生物化学 approach. HIV-1包膜糖蛋白（gp 120）诱导 将研究表达CXCR 4的RBL-2 H3中第二信使的形成。 将评估MAPK和cPLA 2的激活并将其与细胞凋亡相关。 GP 120蛋白诱导细胞迁移的能力。母实验室是 利用HIV-1感染允许的人星形胶质瘤细胞系U87， 用人CD 4和天然或突变的CXCR 4转染，以确定 HIV-1感染中的信号转导和内化。的研究 RBL中的cPLA 2和MAPK将为将其扩展到人提供基础。 细胞系，并确定这些途径的作用 HIV-1感染。

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.