REGULATION OF HIV1 CORECEPTORS CXCR4

趋化因子是趋化细胞因子的一个多样化的基因家族， 通过相互作用调节白细胞的迁移和激活 细胞表面G蛋白偶联受体。他们扮演着重要的角色 类风湿等多种炎症性疾病的病理生理学 关节炎、哮喘和其他肺部疾病。最近，趋化因子 受体CCR5或CXCR4被确定为 人类免疫缺陷病毒HIV-1进入CD4阳性细胞。 虽然CCR5是主要病毒进入的目标，但CXCR4可能是 在从无症状感染发展为艾滋病的过程中发挥重要作用。我们 已经开发出新的细胞模型来理解分子 趋化因子受体的调节机制。趋化因子受体 包括CXCR4在内的基因在大鼠嗜碱性白血病中的功能表达 显示多种白细胞活性的细胞系(RBL-2H3)。这些 研究提供了趋化因子受体交叉调节的证据 彼此在多个层面上发挥作用。 这项提案的总体目标是勾勒出 使用RBL-2H3的CXCR4信号、脱敏和内化 模型系统。磷酸化在信号和信号转导中的作用 受体的脱敏作用将稳定地在RBL-细胞中确定 表达表位标记的天然或突变的CXCR4。结构性的 受体上调节内化的元件将是 已确认身份。CXCR4受体与T嗜性HIV-1膜蛋白的相互作用 糖蛋白(GP120)及其衍生的多肽将被研究。 其他趋化因子受体和黏附分子的作用机制 将对CXCR4功能进行调控，反之亦然。十字 趋化因子受体的调节与差异表达可能 在病理性疾病中负责选择性的白细胞聚集 病毒感染的条件和细胞类型特异性。理解 CXCR4的调控机制将提供新的靶点和 对HIV-1感染者进行治疗干预的更好理由 个人和其他炎症性疾病。

The Chemokines are a diverse gene family of chemotactic cytokines that regulate the migration and activation of leukocytes by interacting with cell-surface G-protein coupled receptors. They play a major role in the pathophysiology of many inflammatory disorders such as rheumatoid arthritis, asthma and other lung diseases. Recently, 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. We have developed novel cellular models for understanding the molecular mechanisms of regulation of chemokine receptors. Chemokine receptors including CXCR4 are functionally expressed in a rat basophilic leukemia cell line (RBL-2H3) which displays many leukocyte activities. These studies have provided evidence that chemokine receptors cross-regulate each other's functions at multiple levels. The overall objective of this proposal is to delineate the pathways of CXCR4 signaling, desensitization and internalization using the RBL-2H3 model system. The role of phosphorylation in signaling and desensitization of the receptors will be determined in RBL-cells stably expressing epitope-tagged native or mutated CXCR4. The structural elements on the receptors that regulate internalization will be identified. Interaction of CXCR4 receptors with T-tropic HIV-1 envelope glycoprotein (GP120) and the peptides derived from it will be studied. The mechanisms by which other chemokine receptors and adhesion molecules regulate CXCR4 function and vice versa will be investigated. Cross regulation of chemokine receptors along with differential expression may be responsible for selective leukocyte accumulation in pathological conditions and cell type specificity in viral infection. Understanding the mechanism by which CXCR4 is regulated will provide novel targets and better rationale for therapeutic intervention in HIV-1 infected individuals and in other inflammatory disorders.