CAPRISA HIV-1 neutralizing antibodies: Harnessing ontogeny for immunogen design

CAPRISA HIV-1 中和抗体：利用个体发育进行免疫原设计

• 批准号: 9197956
• 负责人: Peter D Kwong
• 金额: $ 17.49万
• 依托单位: WITS HEALTH CONSORTIUM (PTY), LTD
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-07 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197956
• 关键词: Acute; Address; Animals; Antibodies; Antibody Binding Sites; Antigens; B-Lymphocytes; Base Sequence; Binding; Cell Culture Techniques; Cell Ontogeny; Cell Separation; Characteristics; Chronic; Cross-Sectional Studies; Development; Epitopes; Event; Evolution; Exposure to; Future; Genes; Glean; Goals; Growth; HIV; HIV Antibodies; HIV vaccine; HIV-1; Immunoglobulin Genes; Immunoglobulins; Individual; Infection; Knowledge; Longitudinal Studies; Longitudinal cohort; Monoclonal Antibodies; Mutagenesis; Mutation; Nature; Passive Immunization; Pathway interactions; Polysaccharides; Property; Research; Sampling; Sampling Studies; Serological; South Africa; Specificity; Structure; Technology; Testing; Time; Transcript; Vaccine Design; Vaccines; Variant; Viral; Virus; Work; base; cohort; design; immunogenic; immunogenicity; in vivo; insight; neutralizing antibody; neutralizing monoclonal antibodies; next generation; next generation sequencing; nonhuman primate; novel; novel vaccines; public health relevance; response; scaffold; tool; vaccine evaluation; virology

 DESCRIPTION (provided by applicant): Animal studies have shown that broadly neutralizing HIV antibodies (bNAbs) can protect against infection, and are likely to be required for an effective HIV vaccine. However, despite over 20 years of research and many different immunogen designs, bNAbs have proven impossible to elicit. In contrast, many studies have confirmed that some HIV-infected individuals naturally develop bNAbs, though normally only after years of infection. Studying these natural examples of bNAbs may provide valuable insights for immunogen design. Most broadly neutralizing monoclonal antibodies (mAbs) isolated thus far have been obtained from cross- sectional screens of chronically infected individuals, which provides limited information on the ontogeny of these bNAbs. However, in the last year the developmental pathways for some bNAbs have been elucidated, by ourselves and others, in studies of longitudinal samples from infected subjects. We hypothesize that these kinds of studies are invaluable in providing an accurate roadmap from elicitation to maturation of bNAbs, with a focus on the very earliest events in their ontogeny. They enable the identification of the antibody precursors and of developmental intermediates, as well as of the viral envelope responsible for eliciting the bNAb lineage. Here, we will focus on bNAbs to the glycan-V2 and -V3 epitopes, which are the most common bNAb targets during the first years of infection. Here, we will use several parallel approaches and technologies to isolate glycan-directed bNAbs from the CAPRISA cohort of subtype C infected donors, and perform mapping and structural studies to define the antibody epitopes. As well as providing valuable tools for our proposed studies, these mAbs will help address the relative dearth of subtype C mAbs, a significant gap in the field as subtype C is the predominant global subtype. Making use of rare stored serial samples from acute infection through to the development of breadth, we will use next generation immunoglobulin gene sequencing to determine the timing of the development of antibody lineages, and to infer an unmutated common ancestor for each lineage. In parallel, viral envelope sequencing at key time points prior to and during the maturation of breadth will enable us to identify viruses that triggered these lineages, and later viral variants that shaped the maturation of breadth. Finally, we will use the knowledge gleaned regarding the ontogeny of bNAbs, to design and characterize novel structure-based immunogens based on envelopes selected specifically for their ability to bind bNAb unmutated common ancestors. In this way, we aim to harness lessons learned from infected people who naturally developed bNAbs, and apply these to the design of an HIV vaccine.

 描述（由申请人提供）：动物研究表明，广泛中和的HIV抗体（bNAb）可以防止感染，并且可能是有效的HIV疫苗所必需的。然而，尽管有超过20年的研究和许多不同的免疫原设计，bNAb已被证明是不可能引发的。相比之下，许多研究已经证实，一些HIV感染者自然会产生bNAb，尽管通常只有在感染数年后才会产生。研究bNAb的这些天然实例可以为免疫原设计提供有价值的见解。迄今为止分离的大多数广泛中和的单克隆抗体（mAb）是从慢性感染个体的横截面筛选中获得的，其提供了关于这些bNAb的个体发生的有限信息。然而，在过去的一年中，一些bNAb的发育途径已经阐明，由我们和其他人，在纵向样本的研究，从感染的主题。我们假设，这些类型的研究是非常宝贵的，在提供一个准确的路线图，从诱导到成熟的bNAb，重点放在最早的事件，在他们的个体发育。它们能够鉴定抗体前体和发育中间体，以及负责引发bNAb谱系的病毒包膜。在这里，我们将重点关注聚糖-V2和-V3表位的bNAb，这是感染最初几年中最常见的bNAb靶点。在这里，我们将使用几种平行的方法和技术，从CAPRISA队列的C亚型感染的供体中分离聚糖导向的bNAb，并进行作图和结构研究，以确定抗体表位。除了为我们提出的研究提供有价值的工具外，这些mAb还将有助于解决C亚型mAb的相对缺乏问题，这是该领域的一个重大空白，因为C亚型是全球主要的亚型。利用从急性感染到广泛发展的罕见储存系列样品，我们将使用下一代免疫球蛋白基因测序来确定抗体谱系发展的时间，并推断每个谱系的未突变共同祖先。同时，在宽度成熟之前和期间的关键时间点进行病毒包膜测序将使我们能够鉴定触发这些谱系的病毒，以及后来形成宽度成熟的病毒变体。最后，我们将使用收集到的关于bNAb个体发育的知识，设计和表征基于包膜的新型结构的免疫原，所述包膜是专门针对其结合bNAb未突变的共同祖先的能力而选择的。通过这种方式，我们的目标是利用从自然产生bNAb的感染者身上学到的经验教训，并将其应用于HIV疫苗的设计。