HIV-1 GP41 ARE RECOGNIZED BY NEUTRALIZING AND NON-NEUTRALIZING ANTIBODIES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心赠款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 HIV-1包膜糖蛋白gp 41经历大的构象变化以驱动病毒和靶细胞膜的融合，从而在病毒进入过程中表现出至少三种不同的构象。针对gp 41的中和抗体通过在融合中间状态下靶向其膜近端外部区域来阻断HIV-1感染。我们已经获得的生化和结构的证据表明，非中和抗体，能够以高亲和力结合到邻近的中和表位在膜近端区域的免疫显性区段，只有承认一个gp 41构象时，膜融合完成。我们提出，这些非中和抗体在HIV-1感染患者中由gp 41抗原以触发的融合后形式诱导，并有助于产生无效的体液应答。这些结果对基于gp 41的疫苗设计具有重要的指导意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. HIV-1 envelope glycoprotein gp41 undergoes large conformational changes to drive fusion of viral and target cell membranes, thereby exhibiting at least three distinct conformations during the viral entry process. Neutralizing antibodies against gp41 block HIV-1 infection by targeting its membrane proximal external region in a fusion-intermediate state. We have obtained biochemical and structural evidence that non-neutralizing antibodies, capable of binding with high affinity to an immunodominant segment adjacent to the neutralizing epitopes in the membrane-proximal region, only recognize a gp41 conformation when membrane fusion is complete. We propose that these non-neutralizing antibodies are induced in HIV-1 infected patients by gp41 antigens in a triggered, postfusion form and contribute to production of ineffective humoral responses. These results have important implications for gp41-based vaccine design by rational strategies.