Antibody Neutralization Mechanisms

抗体中和机制

• 批准号: 9351994
• 负责人: Peter D Kwong
• 金额: $ 216.4万
• 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/9351994
• 关键词: Antibodies; Antigens; B-Lymphocytes; Characteristics; DNA; Data Set; Developmental Process; Enrollment; Epitopes; Frequencies; General Population; Genes; HIV-1; Hemagglutinin; Human; Immune system; Immunization; Influenza A Virus, H5N1 Subtype; Influenza A virus; Memory B-Lymphocyte; Pathway interactions; Prevalence; Publishing; Sorting - Cell Movement; Structure; Transcript; Vaccination; Vaccine Design; Vaccines; Virus; X-Ray Crystallography; base; influenza virus vaccine; interest; neutralizing antibody; next generation sequencing; pathogen; stem; vaccine trial

Viruses such as HIV-1 and influenza A are genetically diverse, complicating their neutralization by antibody. One potential way that antibodies can neutralize broadly is through recognition of a conserved, functionally important component of the virus. We have used X-ray crystallography to investigate the epitopes of broadly neutralizing antibodies and their mechanisms of neutralization. We have also used next generation sequencing to B cell transcript to understand the developmental processed by which broadly neutralizing antibodies mature. Of particular interest for vaccine design are reproducible or convergent antibodies, which have similar modes of recognition and similar B cell ontogenies in multiple donors, as such antibodies might be induced in the general population with a common set of immunogens. While most of our focus has been on HIV-1, we have recently been examining antibodies against other pathogens, including influenza A virus. Antibodies capable of neutralizing divergent influenza A strains could form the basis of a universal vaccine. From subjects enrolled in an H5N1 DNA/MIV-prime-boost influenza vaccine trial, we sorted hemagglutinin cross-reactive memory B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and group 2 influenza A viruses. Co-crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and-in half the subjects-multidonor-class sequences were recovered from >40% of cross-reactive B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies. We propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A immunization strategies.

HIV-1和流感诸如遗传上的病毒在遗传上是多种多样的，使它们的中和抗体复杂化。 抗体可以广泛中和的一种潜在方法是识别病毒的保守，功能上重要的成分。我们已经使用X射线晶体学来研究广泛中和抗体及其中和的机制的表位。我们还使用了下一代测序作为B细胞转录本，以了解通过其广泛中和抗体成熟的发育。疫苗设计特别感兴趣的是可重复的或收敛的抗体，它们在多个供体中具有相似的识别模式和相似的B细胞个体发育，因为在普通种群中可能会诱导这种抗体，具有共同的免疫原子。尽管我们的大部分重点都集中在HIV-1上，但我们最近一直在检查针对其他病原体（包括流感病毒）的抗体。能够中和菌株A菌株的抗体可能构成通用疫苗的基础。在入选H5N1 DNA/MIV-PRIME-BOR-BOOST疫苗试验中的受试者中，我们对血凝素交叉反应记忆B细胞进行了分类，并鉴定了三个抗体类别，每个类别都能中和1组和2组2型流感病毒的多样性亚型。与血凝素蛋白的共结晶结构表明，每个类别都利用特征种系基因和收敛序列基序来识别血凝集素茎中的重叠表位。所有六个分析的受试者均具有至少一个多源类别的序列，而在一半的受试者中，从> 40％的交叉反应性B细胞中回收了一半。相比之下，在已发表的抗体数据集中，这些多元级序列很少见。因此，用发散的血凝素疫苗接种可以增加编码广泛流感A-中和抗体的B细胞的频率。我们提出这些B细胞的序列特征定量流行率是指导普遍流感的免疫策略的度量。