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.

开发可诱导中和抗体 (nAb) 的 HIV 疫苗 仍然是重中之重，近 3 年来该领域的研究已经证明，这是一个 然而，具有适度保护作用的 RV144 疫苗试验的最新结果表明，这是一项艰巨的任务。 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 反应，这种保护可能与功能性抗体 (Abs) 的诱导有关 同样，针对病毒 V2 环上的特定表位进行了 3 多年的研究。 指出了非中和性、先天免疫招募抗体在抗病毒控制和 在过去的 R01 资助期间，疾病进展速度已经变得很明显。 在疫苗诱导的免疫和自然感染的情况下，最有功能的 抗体 (Ab) 反应是由 HIV 特异性 IgG3 Ab 驱动的，但是，这些 IgG3 的作用是什么。 抗体的靶标、这些 IgG3 反应是如何诱导的，以及最关键的是它们如何持续存在 在此，我们勇敢地说一下IgG3长寿的规则。 选择可以从疫苗接种和自然感染中学到，希望 在接触 HIV 之前诱导这些有效的体液效应分子可能 因此，在本申请中，我们建议： 特别剖析了 HIV 特异性 IgG3 反应的特异性和功能特征 根据这些结果，我们将分离出抗原特异性 IgG3 B。 细胞开始学习这些 B 细胞选择特定抗体亚类的“规则” 以及这些反应如何通过佐剂、T 细胞人为地偏向 IgG3 这些研究将抗体功能与 B 细胞编程联系起来。 将提供保护性功能性 Abs 和 定义通过疫苗接种获得保护性免疫力的机制 加强对病毒的控制。