Targeting tonsillar B cells for the induction of effective mucosal immunity to HIV

项目总结/摘要 有效的HIV疫苗可能依赖于足够数量和质量的HIV包膜（Env）特异性抗体。 直肠和阴道粘膜的抗体。口腔粘膜的致敏被认为是一种有前途的方法， 粘膜抗体在HIV进入位点，然而，介导这一过程的机制的理解是 不太了解。我们的项目旨在精确定义诱导膀胱粘膜浆细胞的动力学 通过直接扁桃体内（i.t.）免疫，并根据经验测试策略来调整这一过程，以获得一个 获得保护性HIV疫苗的最佳粘膜抗体谱（定位、广度、功能和持久性） 战略诱导HIV特异性B细胞应答的主要重点是评价佐剂/刺激物， 靶向常规B细胞应答;留下非常规B细胞应答的诱导，包括具有 与粘膜抗体产生的直接相关性在很大程度上未被探索。IgM记忆，一种非传统的B细胞 群体，是IgM记忆，一个主要的第一道防线，对粘膜病原体，并包括异源 亚群，如边缘区和B-1 B细胞，它们是粘膜IgA浆细胞的主要前体。我们 研究已经证明IgM记忆B细胞对急性HIV感染高度应答， 维持与Env特异性抗体的产生高度相关。诱导稳健IgM的机制 记忆疫苗的反应仍然不明确，虽然我们最近的工作已经证明了IL- 9和IL-33，粘膜免疫的已知调节剂，以促进HIV Env特异性 IgM，除了增加Env特异性IgG和IgA应答的广度、幅度和持久性外， 当与有前途的DNA/蛋白质HIV Env免疫原平台VC 10014结合时， 恒河猴体内的中和抗体。我们的核心假设是调节扁桃体 与IL-9或IL-33的微环境将能够快速诱导持久和有效的粘膜体液免疫。 VC10014 HIV疫苗平台的免疫力。这一假设将通过以下具体目标进行检验：1） 确定扁桃体微环境对粘膜体液免疫诱导的影响，2）评估 IL-9或IL-33佐剂化的VC 10014 HIV疫苗平台的保护能力，以及3）确定用于 增强人扁桃体原代B细胞对免疫的应答。该项目将大大促进我们的 深入了解预防艾滋病毒传播和控制保护性疾病发展的机制， 对HIV的体液粘膜反应。

Project Summary/Abstract An effective HIV vaccine is likely to be dependent on sufficient quantity and quality of HIV Envelope (Env)-specific antibody at the rectal and vaginal mucosa. Priming of the oral mucosa is viewed as a promising approach to generate mucosal antibody at HIV entry sites, however the understanding of the mechanisms that mediate this process are poorly understood. Our project seeks to precisely define the dynamics of inducing intestinal-mucosal plasma cells through direct intra-tonsillar (i.t.) immunization, and empirically test strategies to tune this process for obtaining an optimal mucosal antibody profile (localization, breadth, function, and durability) to achieve a protective HIV vaccine strategy. A main emphasis for inducing HIV-specific B cell responses has been to evaluate adjuvants/stimuli that target conventional B cell responses; leaving induction of non-conventional B cell responses, including those with direct relevance to mucosal antibody production largely under-explored. IgM memory, one such unconventional B cell population, is IgM memory, a major first line of defense against mucosal pathogens, and includes heterologous subsets such as marginal zone and B-1 B cells, which are major precursors of mucosal IgA plasma cells. Our research has demonstrated that IgM memory B cells are highly responsive to acute HIV infection and their maintenance is highly correlated with Env-specific antibody development. Mechanisms to induce robust IgM memory vaccine responses remain poorly defined, although our recent work has demonstrated the ability of IL- 9 and IL-33, known regulators of mucosal immunity, to promote the robust development of HIV Env-specific IgM, in addition to increasing the breadth, magnitude, and durability of the Env-specific IgG and IgA response when combined with the promising DNA/protein HIV Env immunogen platform VC10014 which elicits Tier 2 neutralizing antibody in rhesus macaques. Our central hypothesis is that conditioning the tonsil microenvironment with IL-9 or IL-33 will enable the rapid induction of durable and effective mucosal humoral immunity by the VC10014 HIV vaccine platform. This hypothesis will be tested by the following specific aims: 1) Define the effect of the tonsil microenvironment on the induction of mucosal humoral immunity, 2) Evaluate the protective ability of IL-9 or IL-33 adjuvanted VC10014 HIV vaccine platform, and 3) Identify strategies for enhancing human tonsil primary B cell responses to immunization. This project will significantly advance our insight into preventing HIV transmission and the mechanisms that control the development of protective humoral mucosal responses to HIV.