Marginal Zone B Cell Response to HIV

边缘区 B 细胞对 HIV 的反应

• 批准号: 7462489
• 负责人: Raul Martin Torres
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7462489
• 关键词: Adult; Agonist; Animals; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigens; Attention; B-Lymphocyte Subsets; B-Lymphocytes; Cellular biology; Developed Countries; Developing Countries; Epitopes; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; Human; Immune; Immunization; In Vitro; Individual; Infection; Location; Lymphocyte; Lymphoid; Mature B-Lymphocyte; Molecular; Mucous Membrane; Mus; Phenotype; Population; Production; Property; Recruitment Activity; Role; Time; Toll-like receptors; Vaccine Design; Vaccines; Viral; Virus; autoreactivity; base; chemokine; defined contribution; design; experience; immunogenicity; improved; in vitro Model; in vivo; insight; mouse model; neutralizing antibody; particle; receptor; research study; response; virus envelope

DESCRIPTION (provided by applicant): The human immunodeficiency virus (HIV) continues to annually infect millions individuals with most of these infections in developing countries where current anti- retroviral therapy is not readily available or affordable. However, prospects for an effective vaccine remain viable and realistic as HIV-specific antibodies have been isolated from infected individuals that are able to confer immune protection. Moreover, our understanding about how the different mature B cell populations mount antibody responses to foreign antigen has also advanced. Thus, we argue that current vaccine strategies should be able to selectively call upon these distinct B cell subsets to elicit an appropriate anti-viral antibody response. This application, therefore, considers the mechanisms by which distinct B cell subsets mount antibody responses to propose experiments designed to enhance the production of HIV neutralizing antibodies. A major goal of this proposal is to determine whether marginal zone B cells are able to participate in the antibody response to HIV and, if so, do they participate and, if not, can they be recruited to participate. To accomplish this goal in two specific aims, we rely on in vivo and in vitro mouse models of antibody production to molecularly and functionally define the HIV envelope-specific antibodies produced by different B cell subpopulations. Specific Aim 1 characterizes the phenotype of HIV envelope-specific B cells in na¿ve and immunized mice and the antibodies they produce with respect to polyreactivity, autoreactivity and neutralization capability. In Specific Aim 2 we center our attention on the toll-like receptors expressed by B cells and how agonists specific for these receptors alter, if at all, the type of B cells recruited into the HIV antibody response and the molecular and functional properties of the antibodies produced by these cells. Human and mouse marginal zone B cells are phenotypically and functionally similar, thus we consider the use of a mouse model to study the role of marginal zone B cells in the antibody response to HIV to be appropriate. More importantly, a comparable study of human marginal zone B cells is not feasible. Thus, these experiments investigating the principles of how distinct B cell populations respond to HIV in na¿ve and immunized mice will be directly relevant to human B cell biology and will provide significant insight into HIV vaccine design strategies. The need for an effective human immunodeficiency virus (HIV) vaccine is imperative as HIV continues to infect millions of individuals annually. This proposal outlines experiments that will define the contribution of different types of B lymphocytes in the production of antibodies specific for this virus. The information gained by this study will be directly relevant to considerations in HIV vaccine design.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）每年继续感染数以百万计的人，其中大部分感染发生在发展中国家，而这些国家目前的抗逆转录病毒疗法不易获得或负担不起。然而，有效疫苗的前景仍然可行且现实，因为已经从感染者中分离出能够提供免疫保护的艾滋病毒特异性抗体。此外，我们对不同成熟 B 细胞群如何对外源抗原产生抗体反应的理解也有所进展。因此，我们认为当前的疫苗策略应该能够选择性地调用这些不同的 B 细胞亚群来引发适当的抗病毒抗体反应。因此，本申请考虑了不同 B 细胞亚群产生抗体反应的机制，以提出旨在增强 HIV 中和抗体产生的实验。该提案的一个主要目标是确定边缘区 B 细胞是否能够参与针对 HIV 的抗体反应，如果是，它们是否参与，如果不是，是否可以招募它们参与。为了实现这一目标的两个具体目标，我们依靠抗体产生的体内和体外小鼠模型，从分子和功能上定义不同 B 细胞亚群产生的 HIV 包膜特异性抗体。具体目标 1 描述了幼鼠和免疫小鼠中 HIV 包膜特异性 B 细胞的表型以及它们产生的抗体的多反应性、自身反应性和中和能力。在具体目标 2 中，我们将注意力集中在 B 细胞表达的 Toll 样受体上，以及这些受体特异性激动剂如何改变（如果有的话）招募到 HIV 抗体反应中的 B 细胞类型以及这些细胞产生的抗体的分子和功能特性。人类和小鼠边缘区 B 细胞在表型和功能上相似，因此我们认为使用小鼠模型来研究边缘区 B 细胞在 HIV 抗体反应中的作用是合适的。更重要的是，对人类边缘区 B 细胞进行类似研究是不可行的。因此，这些实验研究了不同 B 细胞群如何在初始小鼠和免疫小鼠中对 HIV 做出反应的原理，这将与人类 B 细胞生物学直接相关，并将为 HIV 疫苗设计策略提供重要的见解。由于艾滋病毒每年继续感染数百万人，因此迫切需要一种有效的人类免疫缺陷病毒 (HIV) 疫苗。该提案概述了一些实验，这些实验将确定不同类型的 B 淋巴细胞在产生针对该病毒的特异性抗体中的贡献。这项研究获得的信息将直接与艾滋病毒疫苗设计的考虑因素相关。