MOLECULAR BASIS OF CHEMOKINE RECEPTOR FUSOGENIC ACTIVITY

趋化因子受体融合活性的分子基础

• 批准号: 2672993
• 负责人: Stephen Peiper
• 金额: $ 32.84万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672993
• 关键词: African American; Asian Americans; G protein; HIV envelope protein gp120; antireceptor antibody; cell line; chemokine; chimeric proteins; cofactor; cytokine receptors; human immunodeficiency virus 1; human tissue; laboratory mouse; membrane fusion; monoclonal antibody; protein signal sequence; protein structure function; receptor binding; receptor expression; virulence; virus infection mechanism

DESCRIPTION: Understanding the mechanisms for HIV-1 pathogenesis may be important for the development of strategies to control infection. The initiating events of viral infections are cytoadhesion and membrane fusion. Several viruses, exploit heptahelical receptors as cellular fusigens. Recent data reveals that following interaction with CD4, epitopes unmasked on gp120 env of macrophage (M)-tropic HIV-1 strains bind to a chemokine receptor, CCR5, on the surface of target cells to induce fusion of the viral and cellular lipid bilayers. Chemokine receptors are members of a receptor superfamily which have a seven transmembrane spanning topology and transmit signals through G-proteins. The hypothesis underlying this proposal is that gp120 interacts with sequence motifs in the ectodomains of CCR5 that overlap with those that confer chemokine binding specificity, but that the interaction between gp120 and ccR5 is independent of G-protein signaling. It is further postulated that the binding of gp120 to CCR5 does not transmit a signal through an interaction of its cytosolic domains with G-proteins but that this interaction results in an intramembrane signaling event transmitted through transmembrane spanning domains of the lipid bilayer. This hypothesis will be tested using mutant forms of CCR5 to dissect domains involved in chemokine binding, gp120 binding, env-mediated fusion, and chemokine-induced signaling. The second hypothesis is that there are corollaries to the CCR5 structure function analysis that are disease related. It is postulated that genetic alterations encoding a CCR5 variant with impaired reactivity with gp120 render individuals less susceptible to infection with HIV-1 or alter the course of the disease. The mechanism for the dominant negative effect of the CCR5_(794-825) "knockout" allele in heterozygotes in the Caucasian population will be characterized and novel alleles will be investigated in highly exposed persistently seronegative individuals of African ancestry. The expression of CCR5 fusigenic activity in adult human and fetal mouse tissues will be determined to provide perspective for the molecular analysis of CCR5 fusion activity. Insight into the mechanisms involved in gp120-mediated fusion to target cells through CCR5 may provide novel strategies for blocking the initial event of HIV-1 infection, raising the possibility of aborting the development of AIDS following exposure to HIV-1.

描述：了解HIV-1发病机制可能是 这对制定控制感染的战略很重要。 的 病毒感染的起始事件是细胞粘附和膜融合。 一些病毒利用七螺旋受体作为细胞融合原。 最近的数据显示，在与CD 4相互作用后，表位暴露， 嗜巨噬细胞（M）HIV-1毒株gp 120 env上与趋化因子结合 受体，CCR 5，在靶细胞的表面上诱导病毒的融合， 和细胞脂质双层。 趋化因子受体是受体的成员 超家族具有七跨膜跨越拓扑结构， 通过G蛋白传递信号 这一提议的假设是， gp 120与CCR 5胞外域中重叠的序列基序相互作用 与那些赋予趋化因子结合特异性的，但是， gp 120和ccR 5之间的相互作用不依赖于G蛋白信号传导。 进一步假设gp 120与CCR 5的结合不传递 通过其胞质结构域与G蛋白相互作用的信号， 这种相互作用导致了膜内信号事件 通过脂质双层的跨膜跨域传递。 这一假设将使用突变形式的CCR 5解剖结构域进行检验 参与趋化因子结合、gp 120结合、env介导的融合， 趋化因子诱导的信号传导。 第二个假设是， CCR 5结构功能分析的推论是疾病 相关. 据推测，编码CCR 5变体的遗传改变 与gp 120的反应性受损使得个体不易受到 感染HIV-1或改变疾病的进程。 机制 CCR 5_（794-825）“敲除”等位基因在 高加索人群中的杂合子将是特征性的和新的 将在高度暴露的持续血清阴性患者中研究等位基因 非洲血统的人。 CCR 5融合活性的表达 将确定在成人和胎儿小鼠组织中提供 CCR 5融合活性的分子分析前景。 洞察力 gp 120介导的与靶细胞融合的机制 通过CCR 5可以提供新的策略来阻断初始事件， HIV-1感染，提高了艾滋病发展流产的可能性 在接触HIV-1之后。