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

重组自然杀伤细胞 (NK) 和粘膜先天淋巴细胞 (ILC) 以获得有效的 HIV 疫苗

• 批准号: 9270328
• 负责人: Namal Liyanage
• 金额: $ 15.64万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-04 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270328
• 关键词: ALVAC; ATAC-seq; Achievement; Acquired Immunodeficiency Syndrome; Adjuvant; Agonist; Aryl Hydrocarbon Receptor; Brassicaceae; Broccoli - dietary; C57BL/6 Mouse; Carbazoles; Cells; Containment; Data; Development; Epigenetic Process; Family; Food; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; Homeostasis; Human; Immunity; Indole-3-Carbinol; Infection; Infection prevention; Innate Immune Response; Interleukin-17; Knowledge; Lead; Ligands; Lymphoid Cell; Macaca mulatta; Mediating; Memory; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Multivariate Analysis; Mus; Natural Immunity; Natural Killer Cells; Oral; Peripheral; Phase; Preventive vaccine; Proteins; Regulatory Element; Risk; Role; SIV; SIV Vaccines; Testing; Vaccination; Vaccines; Vegetables; Virus; adaptive immune response; adaptive immunity; aluminum sulfate; antiretroviral therapy; aryl hydrocarbon receptor ligand; combinatorial; design; experimental study; improved; in vivo; mucosal site; natural killer cell protein 44-kDa; novel; novel strategies; prevent; rectal; response; simian immunodeficiency virus gp120; transcription factor; transmission process; vaccination strategy; vaccine candidate; vaccine efficacy; vaccine trial; vector; vector vaccine

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.

项目摘要 尽管治疗中取得了显着成就，但新的HIV感染率 继续增长，艾滋病仍然是世界上第五大发病率。因此， 开发预防HIV传播的有效疫苗或组合方法是 迫切需要。 RV144疫苗试验，该试验使用ALVAC-HIV载体和明矾辅助试验 AIDSVAX B/E GP120蛋白是第一个，到目前为止，唯一的HIV疫苗证明有限但 对艾滋病毒收购的重大保护。虽然大多数艾滋病毒疫苗旨在引起 自适应免疫，疫苗介导的先天免疫反应被忽略了。艾滋病病毒 感染主要发生在粘膜部位，在系统性之前形成局部焦点 病毒的传播。因此，增强粘膜免疫将是预防的有效方法 感染。越来越多的证据表明自然杀伤细胞（NK）和先天性的潜在作用 HIV遏制中的淋巴样细胞-3（ILC3）及其调节适应性免疫的能力 反应和粘膜稳态。安装保护性NK细胞响应并增强 通过增强ILC3功能的粘膜免疫力将是预防的有效方法 感染。但是，关于HIV疫苗诱导的外周NK细胞和粘膜知之甚少 ILC3响应。据我们所知，没有疫苗研究重点是调节NK或ILC3 改善免受艾滋病毒感染的保护。我们概括了在 使用相同的疫苗接种策略，RV144猕猴中的试验。我的初步数据 证明周围和粘膜中早期和耐用的NK和ILC3响应的诱导 疫苗接种后的站点和IL-17之间产生NKP44+ILC的相关性 多变量分析中感染风险降低。因此，我假设ALVAC-SIV GP120/明矾疫苗与增强的NK和ILC3反应相结合，将增强 针对HIV/SIV感染的疫苗功效。为了检验这一假设，我将研究 使用C57BL/6 老鼠。下一 通过与芳基相互作用调节ILC3功能，与增强的粘膜免疫结合 肠道中ILC3的碳氢化合物受体（AHR）可以增强对HIV感染的保护 使用人源化的BLT小鼠。这项研究的结果将增强我们对 艾滋病毒期间系统性和粘膜部位的先天和适应性反应之间的相互作用 疫苗。我设想中等保护性疫苗与增强粘膜的结合 通过与AHR相互作用通过调节NK/ILC3的免疫力将被认为是一种新型HIV 预防疫苗方法。这些结果最终将导致保护性的发展 艾滋病毒疫苗策略针对人类。