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。2012年，我们发表了V1V2区域的结构；这个结构揭示了gp120糖蛋白最后一个未知部分的结构；2014年，我们发表了第一个完整的原子水平的前融合闭合HIV-1 Env三聚体结构；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，我们发表了一个完全糖基化的Env三聚体的结构；这个结构揭示了所有针对预融合闭合三聚体的抗体都必须克服糖蛋白掩蔽；2020年，我们共同发表了病毒粒子上的Env三聚体的冷冻电子断层图。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，包括疟疾、拉萨病毒或最近出现的SARS-CoV-2如何逃避体液免疫反应。其中一些研究涉及结构中立的研究，而另一些涉及蛋白质在其结构域中的传播，以及对这些结构域的免疫反应的映射。

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 2012, we published the structure of the V1V2 region; this structure revealed the domain structure of the last unknown portion of the gp120 glycoprotein; 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 structure of a fully glycosylated Env trimer; this structure revealed how all antibodies that target the prefusion closed trimer must overcome glycan masking; and in 2020, we co-published the cryo-electron tomogram of the Env trimer on virions. 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 malaria, lassa virus or the recently emerged SARS-CoV-2, evade the humoral immune response. Some of these investigations involve strucutral investigations, whereas others involve the dissemination of proteins into their domains, and the mapping of immune responses to those domains.