Targeting IgM Memory to Establish Protective B Cell Responses to HIV

靶向 IgM 记忆以建立针对 HIV 的保护性 B 细胞反应

• 批准号: 9020204
• 负责人: James J Kobie
• 金额: $ 53.35万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020204
• 关键词: Acute; Adoptive Transfer; Affinity; Antibodies; Antibody Response; Antigen Presentation; Antigens; B-Lymphocytes; Blood; Characteristics; Complement Activation; DNA; Data; Dengue; Development; Dissection; Future; HIV; HIV Infections; HIV vaccine; Half-Life; Human; Immune response; Immunization; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulin-Secreting Cells; Immunoglobulins; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Influenza; Interleukin-9; Investigation; Kinetics; Life; Macaca mulatta; Mediating; Memory; Memory B-Lymphocyte; Methods; Mus; Phase; Population; Prevention; Preventive vaccine; Property; Proteins; Signal Transduction; T-Lymphocyte; Testing; Transforming Growth Factor beta; Vaccination; Vaccines; Virus; Work; antibody-dependent cell cytotoxicity; base; cytokine; immunogenicity; in vivo; insight; mucosal site; neutralizing antibody; nonhuman primate; novel; prevent; public health relevance; research clinical testing; research study; response; simian human immunodeficiency virus; transmission process; vaccination strategy

 DESCRIPTION (provided by applicant): Inducing a protective antibody (Ab) response to HIV Envelope (Env) is a major strategy for vaccine-mediated prevention. The occurrence of HIV broadly neutralizing antibodies (bNAb) during HIV infection demonstrates the capability of the human immune response; however, defining the developmental queues of bNAb development and recapitulating their induction and persistence by vaccination remains elusive. Our work has begun to define the B cell features associated with HIV bNAb and protection in humans and non-human primates. The primary focus for studying HIV-specific B cell responses thus far has been IgG and IgA, however relatively minimal investigation has been focused on the contribution of IgM memory to effective HIV-specific responses. Within the human IgM memory population, subsets have been identified in blood including "marginal-zone-like" and "B1-like" B cells, however the inter-relationships between these functionally and phenotypically overlapping populations remains unclear. B cells at mucosal sites include abundant IgM producing antibody-secreting cells (ASC), and half of the mucosal IgA is derived from B-1 B cells. Our previous work has demonstrated the unique characteristics of HIV Env-specific IgM memory B cells in humans and its association with the incidence of bNAbs in HIV-infected subjects and broader Env reactivity in HIV vaccinees. Numerous features of IgM memory suggest that with adequate engagement it could be a valuable contributor to an effective B cell response to HIV. These features include their rapid response, unique and polyreactive immunoglobulin repertoire, neutralizing activity, expansive mucosal distribution, strong complement activation, and enhanced antigen presentation abilities. Additionally, IgM antibodies have been shown to contribute to neutralizing Ab responses against many other viruses. The ability of IgM memory B cells to differentiate upon antigen-stimulation into IgG (and IgA) memory and ASC populations may contribute to qualitatively distinct Ab responses. Mechanisms to induce robust IgM memory responses to protein antigens remain poorly defined and current strategies to induce protective humoral response to HIV may have limited ability to induce beneficial Env-specific IgM memory. Our central hypothesis is that immunization strategies that induce robust Env-specific IgM memory responses will enhance protection from HIV infection. This hypothesis will be tested by the following specific aims: 1) to optimize strategies for the induction of HIV Env-specific IgM memory utilizing in vivo mouse experiments, 2) to determine the protective activity of HIV Env-specific IgM responses in rhesus macaques through an immunogenicity and challenge experiment and 3) to characterize human HIV Env-specific IgM memory through in-depth phenotypic and functional profiling. This project will significantly advance our insight into preventing HIV transmission and the mechanisms that control the development of protective humoral responses to HIV.

 描述（由申请方提供）：诱导针对HIV包膜（Env）的保护性抗体（Ab）应答是疫苗介导预防的主要策略。在HIV感染期间HIV广泛中和抗体（bNAb）的出现证明了人类免疫应答的能力;然而，定义bNAb发展的发展队列并通过疫苗接种重现其诱导和持续性仍然是难以捉摸的。我们的工作已经开始定义与HIV bNA B b相关的B细胞特征以及在人类和非人灵长类动物中的保护。迄今为止，研究HIV特异性B细胞应答的主要焦点是IgG和伊加，然而，相对较少的研究集中在IgM记忆对有效的HIV特异性应答的贡献上。在人IgM记忆群体中，已经在血液中鉴定了包括“边缘区样”和“B1样”B细胞的亚群，然而这些功能和表型重叠群体之间的相互关系仍然不清楚。粘膜部位的B细胞包括丰富的IgM产生抗体分泌细胞（ASC），并且粘膜伊加的一半来源于B-1 B细胞。我们以前的工作已经证明了人类中HIV Env特异性IgM记忆B细胞的独特特征及其与HIV感染受试者中bNAb的发生率和HIV疫苗接种者中更广泛的Env反应性的相关性。IgM记忆的许多特征表明，在充分参与的情况下，它可能是有效的B细胞对HIV应答的有价值的贡献者。这些特征包括其快速反应、独特的多反应性免疫球蛋白库、中和活性、广泛的粘膜分布、强补体激活和增强的抗原呈递能力。此外，IgM抗体已被证明有助于中和针对许多其他病毒的Ab应答。IgM记忆B细胞在抗原刺激后分化成IgG（和伊加）记忆和ASC群体的能力可能有助于定性地区分Ab应答。诱导对蛋白质抗原的稳健IgM记忆应答的机制仍然不清楚，并且诱导对HIV的保护性体液应答的当前策略可能具有有限的诱导有益的Env特异性IgM记忆的能力。我们的中心假设是，诱导强大的Env特异性IgM记忆应答的免疫策略将增强对HIV感染的保护。该假设将通过以下特定目的进行检验：1）利用体内小鼠实验优化诱导HIV Env特异性IgM记忆的策略，2）通过免疫原性和攻毒实验确定恒河猴中HIV Env特异性IgM应答的保护活性，3）通过深入的表型和功能分析表征人HIV Env特异性IgM记忆。该项目将大大提高我们对预防艾滋病毒传播和控制艾滋病毒保护性体液反应发展的机制的认识。