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（由适用提供）：诱导对艾滋病毒包膜（ENV）的受保护抗体（AB）的反应是疫苗介导的预防的主要策略。 HIV感染期间HIV广泛中和抗体（BNAB）的发生证明了人类免疫响应的能力。但是，定义BNAB发育的发展队列并概括了其疫苗的诱导和持久性仍然难以捉摸。我们的工作已经开始定义与HIV BNAB相关的B细胞特征以及人类和非人类原发性的保护。迄今为止，研究HIV特异性B细胞反应的主要重点是IgG和IgA，但是相对最小的投资集中在IGM记忆对有效HIV特异性反应的贡献上。在人类IgM记忆群中，已经在血液中鉴定出子集，包括“边缘区域样”和“ B1样” B细胞，但是这些功能和表型重叠种群之间的相互关系仍然不清楚。粘膜位点的B细胞包括大量的IgM产生抗体分泌细胞（ASC），粘膜IgA的一半来自B-1 B细胞。我们以前的工作证明了HIV ENV特异性IgM记忆B细胞在人类中的独特特征，以及其与HIV感染受试者中BNAB的发生率和HIV疫苗中更广泛的环境反应性的相关性。 IgM记忆的许多特征表明，通过足够的参与度，这可能是有效B细胞反应艾滋病毒的有价值的。这些功能包括它们的快速响应，独特的和多反应性免疫球蛋白库，中和活性，广泛的粘膜分布，强大的完成激活和增强的抗原表现能力。另外，IgM抗体已被证明有助于对许多其他病毒进行中和AB反应。 IgM记忆B细胞在抗原刺激中分化为IgG（和IgA）内存和ASC种群的能力可能有助于质量上不同的AB反应。诱导IgM记忆对蛋白质抗原的鲁棒性记忆反应的机制仍然很差，并且当前诱导对HIV的保护性体液反应的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ENV特异性IGM记忆反应的免疫抑制策略将增强免受HIV感染的保护。该假设将通过以下特定目的进行检验：1）优化在体内实验中诱导HIV ENV ENV特异性IGM记忆利用率，2）确定HIV ENV ENV特异性IgM响应在恒河体误导下通过免疫性和挑战实验的恒星型猕猴的保护和3）来表征人类HHIV的人类IGM IGM igm igm igm igm igm igm igm igm swiment actection Igm响应。分析。该项目将大大提高我们对防止艾滋病毒传播的见解以及控制受保护的艾滋病毒反应发展的机制。