Demystifying the antiviral activity of the IgG3+ antibody response

虽然开发一种可以诱导中和抗体(NAB)的艾滋病毒疫苗 仍然是重中之重，这一领域近30年的研究证明，这是一种 艰巨的任务。然而，最近来自适度保护性RV144疫苗试验的结果认为 在没有nabs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，以及这种保护，可能与诱导功能性抗体(Abs)有关 以病毒V2环上的特定表位为靶点。同样，30多年的研究 指出了非中和的、先天免疫招募抗体在抗病毒控制和 延缓疾病的发展。有趣的是，在过去的R01资助期内，情况变得很明显 在疫苗诱导免疫和自然感染的背景下，最具功能的 抗体(Ab)反应由HIV特异性IgG3抗体驱动。然而，这些IgG3 抗体的靶点，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 一些患者的定义尚未确定。在这里，我们假设长寿的IgG3的规则 可以从接种疫苗和自然感染中学习选择，希望 在接触HIV之前诱导这些有效的体液效应器分子可能 导致持久的保护免受感染。因此，在本申请中，我们建议 具体剖析HIV特异性IgG3应答的特异性和功能 无论是感染还是疫苗接种。基于这些结果，我们将分离出抗原特异性的IgG3B 细胞开始学习这些B细胞选择特定抗体亚类作为 以及这些反应如何通过辅助剂T细胞人为地向IgG3倾斜 帮助，和/或细胞因子。总之，这些研究将抗体功能与B细胞编程联系起来 将提供一流的保护性功能抗体和 确定通过接种疫苗可激发保护性免疫的机制 加强了对病毒的控制。

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.