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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 HIV-1包膜糖蛋白gp41经历了巨大的构象变化，以驱动病毒和靶细胞膜的融合，从而在病毒进入过程中至少表现出三种不同的构象。针对gp41的中和抗体通过靶向其处于融合中间状态的膜近端外部区域来阻断HIV-1感染。我们已经获得了生化和结构证据，非中和抗体能够与膜近端中和表位附近的免疫优势片段高亲和力结合，只有在膜融合完成时才能识别gp41构象。我们认为，这些非中和抗体是由gp41抗原以触发的融合后形式在HIV-1感染患者中诱导的，并有助于产生无效的体液反应。这些结果对理性策略设计基于gp41的疫苗具有重要意义。

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.