MOLECULAR BASIS OF CHEMOKINE RECEPTOR FUSOGENIC ACTIVITY

描述：了解HIV-1致病机制可能需要 对于制定控制感染的战略很重要。这个 病毒感染的起始事件是细胞黏附和膜融合。 有几种病毒利用七螺旋受体作为细胞融合蛋白。 最近的数据显示，在与CD4相互作用后，表位被揭开 巨噬细胞(M)嗜性HIV-1毒株gp120膜蛋白与趋化因子结合 靶细胞表面受体CCR5诱导病毒融合 和细胞脂双层。趋化因子受体是受体的成员 具有七个跨膜跨膜拓扑并传输的超家族 通过G蛋白传递信号。这一提议背后的假设是 Gp120与CCR5重叠胞外域中的序列基序相互作用 那些赋予趋化因子结合特异性的基因，但 Gp120和CCR5之间的相互作用不依赖于G蛋白信号。 进一步假设gp120与CCR5的结合不会传递 通过其胞浆结构域与G蛋白相互作用而产生的信号 这种相互作用导致了膜内信号事件 通过跨膜跨脂双层结构域传播。 这一假设将用CCR5的突变形式进行验证，以剖析结构域 参与趋化因子结合、gp120结合、env介导的融合以及 趋化因子诱导的信号。第二个假设是，有 CCR5结构功能分析的推论是疾病 相关的。据推测，编码CCR5变体的基因改变 与gp120的反应性受损使个人不太容易患上 感染HIV-1或改变疾病进程。该机制的目的是 CCR5_(794-825)“基因敲除”等位基因的显性负效应 高加索人群中的杂合子将具有特征和新颖性 将对持续血清阴性的高暴露人群进行等位基因调查 非洲血统的人。CCR5融合蛋白的表达 在成年人类和胎鼠组织中将被确定为提供 CCR5融合活性的分子分析展望。洞察力 探讨gp120介导的靶细胞融合的机制 通过CCR5可以提供阻止初始事件的新策略 HIV-1感染，增加了流产艾滋病发展的可能性 在接触HIV-1之后。

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.