Defining Neutralization Breadth in HIV+ Human Serum

定义 HIV 人血清中的中和广度

• 批准号: 7761618
• 负责人: PAUL W. SPEARMAN
• 金额: $ 38.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761618
• 关键词: Accounting; Antibodies; Antibody Formation; Antibody Specificity; Avidity; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; Clinical; Clonality; Communities; Complement; Epitope Mapping; Epitopes; Flow Cytometry; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; Human; Individual; Infection; Infection prevention; Isoelectric Focusing; Macaca; Maps; Peripheral; Persons; Phenotype; Population; Reagent; Recombinants; Role; Serum; Specificity; Techniques; Treatment Protocols; Vaccination; Vaccines; Viral; Viral Load result; Virus; base; cohort; defined contribution; design; human monoclonal antibodies; insight; monomer; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; protective efficacy; receptor; response

DESCRIPTION (provided by applicant): HIV vaccine strategies have not yet succeeded in generating broadly neutralizing antibody responses in humans. A limited number of broadly neutralizing human monoclonal antibodies against HIV have been identified and have been the subject of intensive study. Combinations of such antibodies can protect macaques from infection with SIV/HIV chimeric virus, suggesting that if they could be elicited in uninfected humans through vaccination, they could provide protective efficacy. These antibodies may be rare in infected humans, however. In contrast, HIV-infected individuals who demonstrate substantial breadth of neutralization in serum are not rare. We hypothesize that a polyspecific response develops during infection in a substantial subset of individuals and accounts for neutralization breadth. The major goal of this proposal is to define the polyspecific response to HIV present in sera from HIV+ individuals with broad neutralizing antibody responses, and to compare the neutralizing antibody specificities with those who demonstrate narrow neutralization breadth. To do this, we will first define the relationship between envelope trimer binding, avidity, and breadth of neutralization using a novel VLP-based assay. We will determine if trimer-specific antibody responses contribute substantially to the breadth of neutralization in polyclonal serum through antibody depletion techniques and epitope mapping. The clonality of the neutralizing antibody response will be determined for broad and narrow neutralizers. Serum analysis will be complemented by the analysis of B cell subsets identified by VLP binding, and phenotypes associated with broad vs. narrow neutralization will be identified. Together, these studies will enlighten our understanding of neutralization breadth and contribute to the design of a neutralizing antibody-based vaccine regimen. It is very likely that an effective HIV vaccine will need to generate neutralizing antibody responses that can prevent infection with the types of HIV that are circulating in the community. It has been very difficult to generate such broad neutralizing responses using standard vaccine techniques. In this project, we will study the antibody responses in individuals who are infected with HIV who have evidence of broad neutralizing responses. By understanding in detail the antibody responses present in these HIV-infected individuals, we will gain insights into how we can better design a protective HIV vaccine that can generate similar responses in uninfected persons.

描述（由申请人提供）：HIV 疫苗策略尚未成功地在人类中产生广泛的中和抗体反应。已鉴定出有限数量的广泛中和人类艾滋病毒单克隆抗体，并已成为深入研究的主题。此类抗体的组合可以保护猕猴免受 SIV/HIV 嵌合病毒的感染，这表明如果可以通过疫苗接种在未感染的人类中引发这些抗体，那么它们可以提供保护功效。然而，这些抗体在受感染的人类中可能很少见。相比之下，血清中表现出广泛的中和作用的艾滋病毒感染者并不罕见。我们假设大部分个体在感染过程中会产生多特异性反应，并解释了中和广度。该提案的主要目标是定义对具有广泛中和抗体反应的 HIV+个体血清中存在的 HIV 的多特异性反应，并将中和抗体特异性与表现出窄中和宽度的抗体特异性进行比较。为此，我们将首先使用基于 VLP 的新型测定来定义包膜三聚体结合、亲合力和中和广度之间的关系。我们将通过抗体耗竭技术和表位作图来确定三聚体特异性抗体反应是否对多克隆血清中的中和广度有重大贡献。将确定宽中和剂和窄中和剂的中和抗体反应的克隆性。血清分析将通过对 VLP 结合鉴定的 B 细胞亚群的分析进行补充，并且将鉴定与宽中和和窄中和相关的表型。总之，这些研究将启发我们对中和广度的理解，并有助于设计基于中和抗体的疫苗方案。有效的艾滋病毒疫苗很可能需要产生中和抗体反应，以预防社区中流行的艾滋病毒类型的感染。使用标准疫苗技术很难产生如此广泛的中和反应。在这个项目中，我们将研究感染艾滋病毒的个体的抗体反应，这些人有广泛的中和反应的证据。通过详细了解这些艾滋病毒感染者体内存在的抗体反应，我们将深入了解如何更好地设计一种保护性艾滋病毒疫苗，使其在未感染者中产生类似的反应。