Demystifying the antiviral activity of the IgG3+ antibody response

揭秘 IgG3 抗体反应的抗病毒活性

• 批准号: 10556321
• 负责人: Boris Dominik Juelg
• 金额: $ 60.48万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10556321
• 关键词: Adjuvant; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Cytotoxic T-Lymphocytes; Development; Disease Progression; Epitopes; Evolution; Exposure to; Funding; Goals; HIV; HIV vaccine; Humoral Immunities; IgG3; Immune; Immune system; Immunity; Infection; Learning; Link; Mediating; Patients; Research; Role; Specificity; T cell response; T-Lymphocyte; Vaccination; Viral; Viral Physiology; Virus; cytokine; neutralizing antibody; programs; recruit; response; vaccine trial; vaccine-induced immunity

While the development of an HIV vaccine that can induce neutralizing antibodies (nAbs) remains a top priority, nearly 3 decades of research in this arena has proven that this is a daunting task. However, recent results from the modestly protective RV144 vaccine trial argue that protection from infection can be achieved in the absence of nAbs and cytotoxic T cell responses, and this protection and may be linked to the induction of functional antibodies (Abs) that target specific epitopes on the viral V2 loop. Likewise, more than 3 decades of research have pointed to a role for non-neutralizing, innate immune–recruiting Abs in antiviral control and slower disease progression. Interestingly, over the last R01 funding period, it has become clear that in both the setting of vaccine-induced immunity and natural infection, the most functional antibody (Ab) responses are driven by HIV-specific IgG3 Abs. However, what these IgG3 antibodies target, how these IgG3 responses are induced, and most critically how they persist in some patients has yet to be defined. Here, we hypothesize that the rules of long-lived IgG3 selection can be learned from both vaccination and natural infection, with the hope that the induction of these potent humoral effector molecules prior to exposure to HIV may lead to durable protection from infection. Therefore, in this application, we propose to specifically dissect the specificity and functional profile of the HIV-specific IgG3 responses in both infection and vaccination. Based on these results, we will isolate antigen-specific IgG3 B cells to begin to learn the “rules” by which these B cells select a particular antibody subclass as well as how these responses may be artificially skewed towards IgG3 with adjuvants, T cell help, and/or cytokines. Together, these studies, linking antibody function to B cell programming will provide a first-in-class composite picture of the evolution of protective functional Abs and define the mechanisms by which protective immunity may be elicited through vaccination to gain enhanced control over the virus.

而艾滋病毒疫苗的开发可以诱导中和抗体（NABS） 仍然是重中之重，在这个领域进行了将近三十年的研究证明，这是一个 艰巨的任务。但是，受到适度保护的RV144疫苗试验的最新结果争论 在没有NAB和细胞毒性T细胞的情况下，可以实现免受感染的保护 响应和这种保护，可能与功能抗体的诱导有关（ABS） 该靶向病毒V2环上的特定表位。同样，超过30年的研究 已经指出了抗病毒对照中非中和，先天性免疫接收ABS的作用 疾病进展较慢。有趣的是，在过去的R01资金期间，已经变得很清楚 在疫苗诱导的免疫力和自然感染的环境中，这是功能最强的 抗体（AB）反应由HIV特异性IgG3 ABS驱动。但是，这些IgG3是什么 抗体的靶向，这些IgG3反应是如何诱导的，以及最批判性地持续的 一些患者尚未定义。在这里，我们假设长期IgG3的规则 可以从疫苗接种和自然感染中学到选择，希望 在暴露于HIV之前，这些有效的体液效应分子的诱导可能 导致持久的保护免受感染。因此，在此应用程序中，我们建议 特别剖析HIV特异性IgG3响应的特异性和功能曲线 感染和疫苗接种。基于这些结果，我们将隔离抗原特异性IgG3 B 细胞开始学习这些B细胞选择特定抗体亚类的“规则” 以及如何用调节器人为地将这些响应人为地偏向IgG3，T细胞 帮助和/或细胞因子。这些研究将抗体函数与B细胞编程联系起来 将提供保护性功能性ABS的演变的第一类复合图片和 定义可以通过疫苗引起保护的免疫力的机制 增强了对病毒的控制。