Marginal Zone B Cell Response to HIV

边缘区 B 细胞对 HIV 的反应

• 批准号: 7572911
• 负责人: Raul Martin Torres
• 金额: $ 19.25万
• 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/7572911
• 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; Viral Antibodies; Virus; autoreactivity; base; chemokine; defined contribution; design; experience; immunogenicity; improved; in vitro Model; in vivo; insight; meetings; 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（由适用提供）：人类免疫缺陷病毒（HIV）继续每年感染的数百万个患者，其中大多数这些感染在发展中国家，这些人在当前的反网状病毒疗法不容易获得或负担得起的国家中。但是，有效疫苗的前景仍然可行和现实，因为已经从能够允许免疫保护的受感染个体中分离出HIV特异性抗体。此外，我们对不同成熟的B细胞群如何对外国抗原的抗体反应进行了抗体反应的理解也已提高。这就是我们认为，当前的疫苗策略应该能够选择性地呼吁这些不同的B细胞子集，以引起适当的抗病毒抗体反应。因此，该应用考虑了针对旨在增强艾滋病毒中和抗体产生的建议实验的不同B细胞亚群的抗体反应的机制。该提案的一个主要目标是确定边缘区B细胞是否能够参与对艾滋病毒的抗体反应，如果是的话，它们是否参与，如果没有，可以招募他们参加。为了在两个特定目标中实现这一目标，我们依靠体内和体外小鼠的抗体产生模型来分子和功能上定义不同B细胞产生的HIV包膜特异性抗体。特定的目标1表征了Na ve和免疫的小鼠中HIV包膜特异性B细胞的表型以及它们在多反应性，自动反应性和神经化能力方面产生的抗体。在特定的目标2中，我们将注意力集中在B细胞表达的类似Toll样受体上，以及这些受体特异性的激动剂如何改变（如果有的话），募集到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。人和小鼠边缘区B细胞在表型和功能上是相似的，因此我们考虑使用小鼠模型来研究边缘区B细胞在抗体对HIV抗体反应中的作用。更重要的是，对人边缘区B细胞的可比研究是不可行的。这是这些实验，研究了不同B细胞群体对NA¿和免疫小鼠中HIV的反应方式的原理将与人类B细胞生物学直接相关，并将为HIV疫苗设计策略提供重大见解。需要有效的人类免疫缺陷病毒（HIV）疫苗的需要，因为HIV每年继续感染数百万个个体。该建议概述了将定义不同类型B淋巴细胞在该病毒特异性抗体生产中的贡献的实验。这项研究获得的信息将与HIV疫苗设计中的考虑直接相关。