Mechanisms Of Humoral Evasion

设法逃脱体液免疫系统中和的病原体通常是难以接种的疫苗靶标。HIV-1就是这样的病原体之一。虽然HIV-1包膜(Env)是感染期间产生的抗体的主要靶点，但只有一小部分HIV-1感染者会引发广泛的中和抗体，对HIV-1的大部分体液反应由不中和的抗体组成--或以有限的广度和/或效力中和。因此，了解体液逃避的机制可能对开发有效的疫苗至关重要。 我们一直在使用原子级结构研究，无论是通过X射线结晶学还是冷冻电子显微镜(EM)，作为我们了解免疫逃避的Env机制的主要手段。2014年，我们发表了第一个完整的原子水平结构的灌流闭合HIV-1环境三聚体；这个结构揭示了gp41的构象变化，序列变异的位置，以及糖链屏蔽的细节。2016年，我们发表了一种完全糖基化的Env三聚体的晶体结构；这一结构揭示了所有针对灌流闭合三聚体的抗体都必须克服多糖掩蔽。我们现在正在根据分子动力学研究、smFRET研究或其他功能中间体的结构添加更多的结构细节。 除了HIV-1 Env Trimer外，我们还在使用原子级结构研究来确定其他病原体，包括呼吸道合胞病毒(RSV)或最近出现的SARS-CoV-2是如何逃避体液免疫反应的。

Pathogens that manage to evade neutralization by the humoral immune system are often difficult vaccine targets. HIV-1 is one such pathogen. While the HIV-1 envelope (Env) is a primary target for antibodies elicited during infection, only a small minority of HIV-1-infected individuals elicit broadly neutralizing antibodies, and the bulk of humoral responses against HIV-1 consists of antibodies that do not neutralize - or that do so with limited breadth and/or potency. Understanding mechanisms of humoral evasion may therefore be critical to the development of an effective vaccine. We have been using atomic-level structural investigations, either through X-ray crystallography or cryo-electron microscopy (EM), as our primary means for understanding Env mechanism of immune evasion. In 2014, we published the first full atomic-level structure of the prefusion closed HIV-1 Env trimer; this structure revealed gp41 conformational changes, location of sequence variation, and details of the glycan shield. In 2016, we published the crystal structure of a fully glycosylated Env trimer; this structure revealed how all antibodies that target the prefusion closed trimer must overcome glycan masking. We are now adding additional structural details, based on molecular dynamics studies, on smFRET studies, or on structures of additional functional intermediates. In addition to HIV-1 Env trimer, we are also using atomic-level structural investigations to determine how other pathogens, including respiratory syncytial virus (RSV) or the recently emerged SARS-CoV-2 evade the humoral immune response.