Mechanisms Of Humoral Evasion

体液逃避的机制

• 批准号: 7964826
• 负责人: Peter D Kwong
• 金额: $ 16.96万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964826
• 关键词: Antibodies; Binding; Binding Sites; Goals; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Immune; Immune response; Infection; Masks; Methods; Polysaccharides; Site; Structure; Viral; Virus; base; design; interfacial; response

The HIV-1 envelope contains multiply overlapping (and redundant) mechanisms of humoral immune defence. These including glycan shielding, conformational masking, and immunodominant decoys with variable loops. Although explored extensively, many of these mechanisms are still only partially understood. We are using structure-based methods to define them further. In particular, we have investigated how the CD4-binding-site uses conformational masking to hide the conserved site of CD4 binding from most CD4-binding-site-directed antibodies. A portion of the CD4-binding site, however, appears to remain exposed to fulfill an unexpected viral requirement for a rapid CD4 on-rate. We initially presumed that this exposed site related solely to the site of b12 binding, on the alpha-5 helix and outer domain of gp120. However, recent analysis of the a critical part of the CD4 binding site, the interfacial Phe-43 cavity, suggests that part of this site may also be involved in initial attachment.

HIV-1包膜包含多种重叠(和冗余)的体液免疫防御机制。这些包括糖链屏蔽、构象掩蔽和免疫优势诱骗分子的可变环。尽管人们对这些机制进行了广泛的研究，但对其中的许多机制仍只有部分了解。我们正在使用基于结构的方法来进一步定义它们。特别是，我们研究了CD4结合位点如何使用构象掩蔽来对大多数CD4结合位点定向抗体隐藏CD4结合的保守位点。然而，CD4结合位点的一部分似乎仍处于暴露状态，以满足病毒对快速启动CD4的要求。我们最初推测这个暴露的位点只与gp120的α-5螺旋和外部结构域上的B12结合部位有关。然而，最近对CD4结合部位的关键部分，界面Phe-43空腔的分析表明，该部位的一部分也可能参与最初的附着。