Mechanisms Of Humoral Evasion

设法逃避体液免疫系统中和的病原体通常是困难的疫苗靶标。HIV-1就是这样一种病原体。虽然HIV-1包膜（Env）是感染过程中引发抗体的主要靶点，但只有少数HIV-1感染者会引发广泛中和抗体，而针对HIV-1的大部分体液应答由不中和的抗体组成-或者以有限的广度和/或效力这样做。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水平的结构研究，无论是通过X射线晶体学或冷冻电子显微镜（EM），作为我们的主要手段了解免疫逃避的Env机制。2012年，我们发表了V1 V2区域的结构;该结构揭示了gp 120糖蛋白最后一个未知部分的结构域结构; 2014年，我们发表了融合前封闭的HIV-1 Env三聚体的第一个完整的原子水平结构;该结构揭示了gp 41构象变化、序列变异的位置和聚糖屏蔽的细节; 2016年，我们发表了完全糖基化的Env三聚体的结构;该结构揭示了所有靶向融合前封闭三聚体的抗体必须克服聚糖掩蔽; 2020年，我们共同发表了病毒体上Env三聚体的冷冻电子断层扫描图。 我们现在正在添加额外的结构细节，基于分子动力学研究，smFRET研究，或其他功能中间体的结构。 除了HIV-1 Env三聚体，我们还使用原子水平的结构研究来确定其他病原体，包括疟疾，拉沙病毒或最近出现的SARS-CoV-2，如何逃避体液免疫反应。这些研究中的一些涉及结构研究，而另一些则涉及蛋白质向其结构域的传播，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.