Targeting IgM Memory to Establish Protective B Cell Responses to HIV

 描述(由申请人提供)：诱导对HIV包膜(Env)的保护性抗体(Ab)反应是疫苗介导的预防的主要策略。HIV感染期间出现的HIV广谱中和抗体(BNAb)表明了人类免疫反应的能力；然而，定义bNAb发育的发育队列并概述它们通过疫苗接种的诱导和持久性仍然是难以捉摸的。我们的工作已经开始确定与人类和非人类灵长类动物的HIV bNAb和保护相关的B细胞特征。到目前为止，研究HIV特异性B细胞反应的主要焦点是免疫球蛋白和IgA，但相对较少的研究集中在IgM记忆对有效的HIV特异性反应的贡献上。在人类IgM记忆群体中，已在血液中发现了包括“边缘带样”和“B1样”B细胞的亚群，但这些功能和表型重叠的群体之间的相互关系尚不清楚。粘膜部位的B细胞含有丰富的产生抗体的抗体分泌细胞(ASC)，粘膜中半数的IgA来源于B-1B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感染者中bNAbs的发生率和HIV疫苗接种者中更广泛的Env反应性的关系。IgM记忆的许多特征表明，如果有足够的参与，它可能是有效的B细胞对艾滋病毒反应的有价值的贡献者。这些特征包括快速反应、独特的和多反应的免疫球蛋白谱系、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免疫球蛋白(和免疫球蛋白A)记忆和ASC群体的能力可能有助于产生不同的抗体反应。诱导对蛋白质抗原的强大的IgM记忆反应的机制仍然不清楚，目前诱导对HIV的保护性体液反应的策略在诱导有益的Env特异性的IgM记忆方面的能力可能有限。我们的中心假设是，诱导强大的环境特异性IgM记忆反应的免疫策略将增强对艾滋病毒感染的保护。这一假说将通过以下具体目标来检验：1)利用在体小鼠实验来优化诱导HIV环境特异性IgM记忆的策略，2)通过免疫原性和挑战实验来确定HIV环境特异性IgM反应在恒河猴中的保护活性，以及3)通过深入的表型和功能描述来表征人类HIV环境特异性IgM记忆。该项目将极大地促进我们对预防艾滋病毒传播和控制对艾滋病毒的保护性体液反应发展的机制的洞察。

 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.