Retooling Natural killers cells (NK) and mucosal Innate lymphoid cells (ILCs) for an effective HIV vaccine

项目摘要 尽管在治疗方面取得了显著成就，但新的艾滋病毒感染率 艾滋病继续增长，仍是世界第五大发病率。因此， 预防艾滋病毒传播的有效疫苗或组合方法的开发是 急需之物。RV144疫苗试验，使用ALVAC-HIV载体和明胶佐剂 AIDSVAX B/E gp120蛋白是第一种，也是迄今为止唯一一种表现出有限但 对感染艾滋病毒提供了显著的保护。虽然大多数艾滋病毒疫苗的设计都是为了诱导 获得性免疫，即疫苗介导的先天免疫反应一直被忽视。艾滋病病毒 感染主要发生在黏膜部位，在此局部病灶在全身感染之前形成。 病毒的传播。因此，提高黏膜免疫力将是预防和预防 感染。越来越多的证据显示自然杀伤细胞(NK)和先天的潜在作用 HIV遏制中的第三类淋巴细胞(ILC3)及其调节获得性免疫的能力 反应和粘膜动态平衡。增强保护性NK细胞应答和增强 通过增强ILC3的功能进行黏膜免疫将是预防的有效途径 感染。然而，关于HIV疫苗诱导的外周NK细胞和粘膜的情况知之甚少。 ILC3响应。据我们所知，还没有疫苗研究集中在调节NK或ILC3来 加强对艾滋病毒感染的保护。我们已经概括了在 RV144在恒河猴身上进行试验，使用相同的疫苗接种策略。我的初步数据 证明在外周和粘膜中诱导早期和持久的NK和ILC3反应 免疫后的部位和肠道产生IL-17的NKp44+ILCs之间的相关性 在多变量分析中降低感染风险。因此，我假设ALVAC-SIV 接种gp120/明矾疫苗，再加上增强的NK和ILC3反应，将增强 预防HIV/SIV感染的疫苗效果。为了检验这一假设，我将调查 C57BL/6外周和粘膜ILC的ALVAC-SIV gp120加强免疫策略 老鼠。接下来，我将确定ALVAC-HIV gp120/明矾优质疫苗是否促进了疫苗接种， 通过与芳基相互作用调节ILC3功能而增强粘膜免疫 肠道中ILC3的碳氢受体(AhR)可增强对HIV感染的保护作用 使用人源化的BLT小鼠。这项研究的结果将加深我们对 HIV感染期间全身和粘膜部位先天反应和适应性反应之间的相互作用 疫苗。我设想一种中等保护性的疫苗与增强的粘膜相结合 通过与AhR相互作用调节NK/ILC3的免疫将被认为是一种新的HIV 预防性疫苗接种方法。这些结果最终将导致开发一种保护性的 针对人类的艾滋病毒疫苗战略。

Project Summary Despite remarkable achievements in the treatment, the rates of new HIV infections continue to grow, and AIDS remains the fifth largest morbidity in the world. Consequently, the development of an effective vaccine or combinatorial approaches that prevent HIV transmission is urgently needed. The RV144 vaccine trial, which used ALVAC-HIV vector and alum-adjuvanted AIDSVAX B/E gp120 protein, is the first, and so far the only, HIV vaccine to demonstrate limited but significant protection against HIV acquisition. While most HIV vaccines have been designed to elicit adaptive immunity, vaccine-mediated innate immune responses have been overlooked. HIV infection occurs mainly at the mucosal site, where localized foci are formed before the systemic spread of the virus. Thus, enhancing mucosal immunity would be an effective way to prevent infection. Increasing evidence shows the potential role of natural killer cells (NK) and innate lymphoid cells group-3 (ILC3) in HIV containment, and their ability to modulate adaptive immune responses and mucosal homeostasis. Mounting protective NK cell responses and enhancing mucosal immunity by augmenting the functions of ILC3 would be an effective way of preventing infection. However, little is known about HIV vaccine-induced peripheral NK cells and mucosal ILC3 responses. To our knowledge, no vaccine study has focused on modulating NK or ILC3 to improve protection from HIV infection. We have recapitulated the similar protection observed in the RV144 trial in rhesus macaques using the same vaccination strategy. My preliminary data demonstrate the induction of early and durable NK and ILC3 responses in peripheral and mucosal sites following vaccination and a correlation between IL-17 producing NKp44+ILCs in the gut with reduced risk of infection in the multivariate analysis. Thus, I hypothesize that the ALVAC-SIV gp120/alum vaccination, combined with augmented NK and ILC3 responses, would enhance vaccine efficacy against HIV/SIV infection. To test this hypothesis, I will investigate the effect of ALVAC-SIV gp120 prime boost vaccination strategy on peripheral and mucosal ILCs using C57BL/6 mice. Next, I will determine whether the ALVAC-HIV gp120/ alum prime-boost vaccination, combined with augmented mucosal immunity by modulating ILC3 function via interacting with Aryl hydrocarbon receptor (AhR) of ILC3 in the gut can enhance the protection against HIV infection using humanized BLT mice. The results of this study will enhance our understanding of the interplay between innate and adaptive responses in systemic and mucosal sites during HIV vaccine. I envision that the combination of a moderately protective vaccine with enhanced mucosal immunity via modulating NK/ILC3 by interacting with AhR will be recognized as a novel HIV preventive vaccine approach. These results will lead ultimately to the development of a protective HIV vaccine strategy for humans.