Marginal Zone B Cell Response to HIV

描述（由申请人提供）：人类免疫缺陷病毒（HIV）每年继续感染数百万人，其中大多数感染发生在发展中国家，这些国家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，因为从受感染的个体中分离出了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细胞群如何对外来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，本应用考虑了不同的B细胞亚群装载抗体反应的机制，提出了旨在增强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区B细胞是否能够参与对HIV的抗体反应，如果是，它们是否参与，如果不是，它们是否可以被招募参与。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抗体产生的小鼠模型来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。特异性靶标1表征了HIV包膜特异性B细胞的表型，以及它们在多反应性、自身反应性和中和能力方面产生的抗体。在特异性目标2中，我们将重点关注B细胞表达的toll样受体，以及这些受体特异性激动剂如何改变（如果有的话）参与HIV抗体反应的B细胞类型，以及这些细胞产生的抗体的分子和功能特性。人和小鼠的边缘带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细胞的可比研究是不可行的。因此，这些实验研究了不同的B细胞群如何在未接种和免疫的小鼠中对HIV作出反应的原理，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。该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贡献的实验。这项研究获得的信息将与HIV疫苗设计的考虑直接相关。

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.