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: 9222699
• 负责人: James J Kobie
• 金额: $ 80.74万
• 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/9222699
• 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; Immunize; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulin-Secreting Cells; Immunoglobulins; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Influenza; Interleukin-9; Investigation; Kinetics; Macaca mulatta; Mediating; Memory; Memory B-Lymphocyte; Methods; Mus; Phase; Phenotype; Population; Prevention; Preventive vaccine; Property; Proteins; Signal Transduction; T-Lymphocyte; Testing; Transforming Growth Factor beta; Vaccination; Vaccines; Virus; Work; antibody-dependent cell cytotoxicity; base; clinically significant; cross reactivity; cytokine; experimental study; immunogenicity; in vivo; insight; mucosal site; neutralizing antibody; nonhuman primate; novel; prevent; public health relevance; research clinical testing; 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（由申请人提供）：诱导针对 HIV 包膜（Env）的保护性抗体（Ab）反应是疫苗介导预防的主要策略。 HIV感染期间出现的HIV广泛中和抗体（bNAb）表明了人体免疫反应的能力；然而，定义 bNAb 发育的发育队列并通过疫苗接种概括其诱导和持续性仍然难以捉摸。我们的工作已经开始确定与 HIV bNAb 相关的 B 细胞特征以及对人类和非人类灵长类动物的保护。迄今为止，研究 HIV 特异性 B 细胞反应的主要焦点是 IgG 和 IgA，但相对较少的研究集中在 IgM 记忆对有效 HIV 特异性反应的贡献上。在人类 IgM 记忆群体中，已在血液中鉴定出亚群，包括“边缘区样”和“B1 样”B 细胞，但这些功能和表型重叠群体之间的相互关系仍不清楚。粘膜部位的 B 细胞包括丰富的产生 IgM 的抗体分泌细胞 (ASC)，粘膜 IgA 的一半来源于 B-1 B 细胞。我们之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 感染者中 bNAb 的发生率以及 HIV 疫苗接种者中更广泛的 Env 反应性的相关性。 IgM 记忆的众多特征表明，如果充分参与，它可能成为 B 细胞对 HIV 的有效反应的重要贡献者。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、强大的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抗体反应。 IgM 记忆 B 细胞在抗原刺激下分化为 IgG（和 IgA）记忆和 ASC 群体的能力可能有助于产生性质不同的抗体反应。诱导对蛋白质抗原的强烈 IgM 记忆反应的机制仍然不明确，目前诱导对 HIV 的保护性体液反应的策略可能诱导有益的 Env 特异性 IgM 记忆的能力有限。我们的中心假设是，诱导强烈的 Env 特异性 IgM 记忆反应的免疫策略将增强对 HIV 感染的保护。该假设将通过以下具体目标进行检验：1）利用体内小鼠实验优化诱导 HIV 包膜特异性 IgM 记忆的策略，2）通过免疫原性和攻击实验确定恒河猴中 HIV 包膜特异性 IgM 反应的保护活性，3）通过深入的表型和功能来表征人类 HIV 包膜特异性 IgM 记忆 分析。该项目将极大地推进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。