Marginal Zone B Cell Response to HIV

描述(由申请人提供)：在发展中国家，人类免疫缺陷病毒(艾滋病毒)每年继续感染数百万人，其中大多数感染这种感染，因为目前的抗逆转录病毒治疗不容易获得或负担不起。然而，有效疫苗的前景仍然是可行和现实的，因为已经从能够提供免疫保护的感染者身上分离出艾滋病毒特异性抗体。此外，我们对不同成熟B细胞群如何对外来抗原产生抗体反应的理解也有所进步。因此，我们认为目前的疫苗策略应该能够选择性地召唤这些不同的B细胞亚群来诱导适当的抗病毒抗体反应。因此，这项申请考虑了不同的B细胞亚群安装抗体反应的机制，以提出旨在增强HIV中和抗体产生的实验。这项提议的一个主要目标是确定边缘带B区细胞是否能够参与艾滋病毒的抗体反应，如果能够，它们是否参与，如果不参与，是否可以招募它们参与。为了在两个特定的目标上实现这一目标，我们依靠体内和体外小鼠抗体产生的模型，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。特定目的1描述了初治和免疫小鼠中HIV包膜特异性B细胞的表型及其产生的多反应性、自身反应性和中和能力的抗体。在具体目标2中，我们将注意力集中在B细胞表达的Toll样受体以及这些受体的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细胞的类型以及这些细胞产生的抗体的分子和功能特性。人和小鼠的边缘带B细胞在表型和功能上是相似的，因此我们认为使用小鼠模型来研究边缘带B细胞在HIV抗体应答中的作用是合适的。更重要的是，对人类边缘带B细胞进行可比性研究是不可行的。因此，这些实验将直接与人类B细胞生物学相关，并将为HIV疫苗的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，迫切需要一种有效的人类免疫缺陷病毒(艾滋病毒)疫苗。这项提案概述了将确定不同类型的B淋巴细胞在产生针对该病毒的特异性抗体中的作用的实验。这项研究获得的信息将直接与艾滋病毒疫苗设计中的考虑因素相关。

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.