Characterization of T & B cell responses correlated with broad neutralizing Abs

T 的表征

• 批准号: 7663383
• 负责人: Spyros A Kalams
• 金额: $ 53.16万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663383
• 关键词: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Antibodies; Antibody Formation; Autologous; B-Cell Activation; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Chronic; Data; Development; Disease Progression; Early identification; Face; Generations; Goals; HIV; HIV Infections; HIV vaccine; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunity; In Vitro; Individual; Infection; Instruction; Maintenance; Measures; Outcome; Reagent; Role; Sorting - Cell Movement; System; T-Lymphocyte; Testing; Time; Vaccinated; Vaccination; Vaccines; Viral; Viral Proteins; Viremia; Virus; advanced disease; assay development; cohort; design; neutralizing antibody; new technology; programs; response; vaccine candidate; vaccine development

An effective HIV vaccine will need to elicit potent humoral and cellular immune responses for true sterilizing immunity. HIV-specific CD4 + T cell responses, particularly proliferative responses, are a potent correlate of control of viremia, but relatively uncommon and of low magnitude in HIV infected individuals. Autologous neutralizing antibodies in HIV infected subjects are typically of low titer, and lack sufficient breadth to neutralize heterologous viruses. Our current HIV vaccine candidates currently under testing in humans are able to elicit CD8+ cellular immune responses, and may well provide partial protection against infection, but are unlikely to generate neutralizing antibodies. This HIVRAD program project will identify viral sequences that elicit broadly neutralizing antibodies in subjects with varying degrees of control of viremia. This particular project (project 2) will take advantage of our access to a large cohort of subjects with early and chronic HIV infection, and which contains several individuals with control of viremia in the absence of anti-retroviral therapy. From years of expertise studying cellular immune responses, and from our preliminary data, we know several of these individuals have intact virus-specific CD4+ T cell responses. Our goalwith this project is to identify interactions between CD4+ T cells and B cells that predict the ability of HIV-infected individuals to generate broadly neutralizing antibodies. We have also designed new technology that allows us to sort B cells specific for HIV envelope, which we will use to isolate B cell clones from subjects with broadly neutralizing antibody activity. The outcome of this project will be a comprehensive picture of helper function required to maintain B cell responses, assays to assess CD4-B cell function in chronically infected and vaccinated individuals, and new antibody reagents that will be used to further characterize HIV neutralizing activity. RELEVANCE (See instructions): Understanding the factors that allow the generation of broadly neutralizing antibodies is critical to vaccine development. In this project we will explore the hypothesis that intact interactions between T cells and B cells is critical to the development and maintenance of broadly neutralizing antibodies in HIV-infected individuals.

有效的HIV疫苗将需要引起有效的体液和细胞免疫反应以实现 消毒免疫力。 HIV特异性的CD4 + T细胞反应，尤其是增殖反应，是一种有效的 病毒血症的控制相关，但相对罕见和艾滋病毒感染个体的低幅度相关。 艾滋病毒感染受试者中的自体中和抗体通常为低滴度，并且缺乏足够的 广度以中和异源病毒。我们目前正在测试的目前正在测试的HIV HIV疫苗 人类能够引起CD8+细胞免疫反应，并且很可能会提供部分保护 感染，但不太可能产生中和抗体。这个Hivrad计划项目将识别病毒 在病毒血症控制程度不同的受试者中引起广泛中和抗体的序列。 这个特定的项目（项目2）将利用我们访问与早期的大量主题 和慢性艾滋病毒感染，其中包含几个在没有病毒血症的人的情况下 抗逆转录病毒疗法。从研究细胞免疫反应的多年专业知识以及我们的初步 数据，我们知道其中一些人具有完整的病毒特异性CD4+ T细胞反应。我们的队 该项目是确定CD4+ T细胞与B细胞之间的相互作用，以预测HIV感染的能力 个体产生广泛中和抗体。我们还设计了新技术，可以 我们要对特异性的HIV包膜进行分类，我们将使用该细胞将B细胞克隆隔离 广泛中和抗体活性。该项目的结果将是助手的全面图片 维持B细胞反应所需的功能，评估慢性感染中CD4-B细胞功能的测定 和接种疫苗的个体以及新的抗体试剂，这些试剂将用于进一步表征HIV 中和活性。 相关性（请参阅说明）： 了解允许生成广泛中和抗体的因素对于疫苗至关重要 发展。在这个项目中，我们将探讨T细胞与B细胞之间完整相互作用的假设 对于艾滋病毒感染者的广泛中和抗体的开发和维持至关重要。