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

项目摘要/摘要 有效的HIV疫苗很可能依赖于足够数量和质量的针对HIV的包膜(Env) 直肠和阴道粘膜有抗体。口腔粘膜的启动被认为是一种有希望的方法来产生 HIV进入部位的粘膜抗体，然而，对介导这一过程的机制的理解是 人们对此知之甚少。我们的项目试图精确地定义诱导肠粘膜浆细胞的动力学 通过直接扁桃体内(I.T.)免疫接种，并对调整这一过程的策略进行经验测试，以获得 实现保护性HIV疫苗的最佳黏膜抗体图谱(定位、广度、功能和持久性) 策略。诱导HIV特异性B细胞反应的一个主要重点是评估佐剂/刺激 靶向常规B细胞反应；留下非常规B细胞反应的诱导，包括那些 与粘膜抗体产生的直接相关性在很大程度上还没有得到充分的研究。免疫球蛋白记忆，一种这样的非常规B细胞 是免疫球蛋白M记忆，是抵御粘膜病原体的主要第一道防线，包括异源 如边缘区和B-1B细胞等亚群，它们是粘膜IgA浆细胞的主要前体。我们的 研究表明，IgM记忆B细胞对急性HIV感染高度敏感，它们的 维持与环境特异性抗体的产生高度相关。诱导强效IgM的机制 记忆疫苗的反应仍然没有明确的定义，尽管我们最近的工作已经证明了IL- 9和IL-33，已知的粘膜免疫调节剂，促进HIV Env特异性的强劲发展 免疫球蛋白除了增加环境特异性免疫球蛋白和免疫球蛋白A应答的广度、幅度和持久性外 当与前景看好的HIV Env免疫原平台VC10014结合时，VC10014会引发Tier 2 猕猴体内的中和抗体。我们的中心假设是调节扁桃体 使用IL-9或IL-33的微环境将能够快速诱导持久有效的粘膜体液 免疫力由VC10014 HIV疫苗平台提供。这一假设将通过以下具体目标进行检验：1) 确定扁桃体微环境在诱导粘膜体液免疫中的作用，2)评估 IL-9或IL-33佐剂VC10014 HIV疫苗平台的保护能力，以及3)确定策略 增强人类扁桃体初级B细胞对免疫的反应。这个项目将极大地推进我们的 对预防艾滋病毒传播和控制保护性发展的机制的洞察 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.