Mechanisms Of Humoral Evasion

体液逃避的机制

• 批准号: 10273003
• 负责人: Peter D Kwong
• 金额: $ 134.24万
• 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/10273003
• 关键词: 2019-nCoV; Antibodies; Bypass; Cryoelectron Microscopy; Crystallization; Development; Disease; Goals; HIV-1; HIV-1 vaccine; Hepatitis B Virus; Immune Evasion; Immune response; Immune system; Individual; Infection; Influenza A virus; Investigation; Location; Masks; Minority; Molecular Conformation; Polysaccharides; Publishing; Respiratory syncytial virus; Structure; Vaccines; Variant; Virus; X-Ray Crystallography; base; design; human pathogen; molecular dynamics; neutralizing antibody; pathogen; response; single-molecule FRET

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.

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。2014年，我们发表了融合前封闭HIV-1 Env三聚体的第一个完整原子水平结构;该结构揭示了gp 41构象变化，序列变异的位置和聚糖盾的细节。2016年，我们发表了完全糖基化的Env三聚体的晶体结构;该结构揭示了所有靶向融合前闭合三聚体的抗体必须克服聚糖掩蔽。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，包括呼吸道合胞病毒（RSV）或最近出现的SARS-CoV-2如何逃避体液免疫应答。