Role of Follicular T Helper Cells In Enhancing Humoral Immunity and Protection

开发有效的艾滋病疫苗的两个最关键的挑战是了解如何 在粘膜部位诱导持久免疫，并确定艾滋病毒与免疫之间的早期相互作用 系统。在项目3中，我们将使用SIV的恒河猴(RM)模型来解决这两个问题 感染。艾滋病疫苗能够产生保护性免疫的确切机制尚不清楚，但 现在普遍的共识是，一种有效的疫苗应该同时诱导细胞和体液武器。 免疫系统，特别是在粘膜部位。年RV-144艾滋病疫苗试验的最新数据 泰国建议抗体在预防艾滋病毒感染方面发挥潜在作用。一个令人震惊的发现来自于 RV-144试验表明，保护作用是短暂的，主要出现在接种疫苗后的第一年。 因此，开发有效疫苗的一个主要目标是了解如何产生长寿的粘膜 豁免权。(5D4T滤泡辅助细胞(TFH)对于产生有效和持久的抗体至关重要 在这个项目中，我们将确定它们在产生保护性体液免疫中的作用 接种疫苗和感染。 在我们的具体目标1中，我们将检验长期体液免疫至关重要的假设。 依赖于CD4TFH细胞，高效地产生这些细胞是必不可少的 有效的艾滋病毒疫苗的组成部分。我们将检查SIV的规模、质量和持久性 免疫后外周和粘膜部位特异性CD4TFH细胞及其与 B细胞反应。这些研究将检测DNA/MVA免疫的RMS中的CD4 TFH反应 GM-CSF佐剂疫苗(项目1)和TLRs佐剂SIV蛋白疫苗 包裹在纳米颗粒中(项目2)。这些研究将确定哪种疫苗方案最有效 在外周和粘膜部位诱导CD4 TFH细胞以及不同佐剂如何调节TFH 体液免疫应答及其对功能质量和寿命的影响。在我们的具体目标2中， 我们将检验HIV/SIV免疫致病机制通常会阻止发展为 广泛中和抗体反应，但这可以通过免疫来产生强大的TFH来抵消 感染前的反应。我们将测定TFH细胞对SIV感染的敏感性，并研究 接种疫苗对其感染后状态的影响及其与病毒水平的关系 CD4TFH细胞的复制和SIV感染的主要特征，包括对 病毒和艾滋病的进展。

Two of the most critical challenges in developing an effective AIDS vaccine are to understand how to induce durable immunity at mucosal sites and to define the early interactions between HIV and the immune system. In Project 3 we will address both of these issues using the rhesus macaque (RM) model of SIV infection. The precise mechanism by which an AIDS vaccine can confer protective immunity is not known but there is now a general consensus that an effective vaccine should induce both the cellular and humoral arms of the immune system, in particular at the mucosal sites. Recent data from the RV-144 AIDS vaccine trial in Thailand suggest a potential role for antibody in protection from HIV infection. One striking finding from the RV-144 trial was that protection was short-lived and was mostly seen during the first year after vaccination. Thus, a major goal in developing an effective vaccine is to understand how to generate long-lived mucosal immunity. (5D4 T follicular helper (TFH) cells are critical for generating potent and long-lasting antibody responses and in this project we will determine their role in generating protective humoral immunity following vaccination and infection. In our specific aim 1, we will test the hypothesis that long-term humoral immunity is critically dependent on CD4 TFH cells and that the efficient generation of these cells is an essential and obligatory component of an effective HIV vaccine. We will examine the magnitude, quality and persistence of SIV specific CD4 TFH cells in both peripheral and mucosal sites after vaccination and determine its correlation to B cell responses. These studies will examine CD4 TFH responses in RMs immunized with DNA/MVA vaccines adjuvanted with GM-CSF (Project 1) and SIV protein immunizations adjuvanted with TLRs encapsulated in nanoparticles (Project 2). These studies will define which vaccine regimen is most effective in inducing CD4 TFH cells in peripheral and mucosal sites and how the different adjuvants modulate the TFH response and their influence on functional quality and longevity of humoral immunity. In our specific aim 2, we will test the hypothesis that HIV/SIV immunopathogenesis normally precludes the development of a broadly neutralizing antibody response, but this can be counteracted by immunization to generate strong TFH responses before infection. We will determine the susceptibility of TFH cells to SIV infection and study the influence of vaccination on their status following infection, and the relationship between the level of virus replication in CD4 TFH cells and the main features of SIV infection, including the immune response to the virus and the progression to AIDS.