Elicitation of mucosal immune responses against HIV

摘要 人类免疫缺陷病毒（HIV）主要进入宿主并通过粘膜组织引发感染。 因此，能够在粘膜组织中引发细胞和体液免疫反应的疫苗接种策略是 急需。然而，目前还没有批准的佐剂可以实现 T 细胞的稳定水平。 和粘膜组织中的抗体反应。因此，迫切需要一种替代的、有效的、 粘膜疫苗接种的安全策略。我们的长期目标是开发能够 引发针对 HIV-1 的保护性免疫力。我们的目标是设计用于粘膜递送的纳米粒子 HIV-1 抗原并研究其对引发全身和粘膜免疫反应的影响。至 为此，我们开发了一种新的基于脂质的纳米颗粒 (NP) 系统，可以引发强细胞毒性 CD8 T 淋巴细胞 (CTL) 对亚基蛋白抗原作出反应。我们表明这些新疫苗 NP 可以促进 将抗原递送至体内抗原呈递细胞，产生传播至粘膜组织的 CTL， 包括宫颈阴道和胃肠道，并保护动物免受病毒感染。我们还展示 NPs 在小鼠中诱导显着更高的抗体滴度，持续时间 > 400 天，具有更高的亲和力、持久性， 和市场上的传统佐剂（例如明矾或 Montanide）相比。基于这些 初步数据显示，我们建议开发一种新的基于纳米制剂的粘膜免疫策略 对抗 HIV-1。我们将检验我们的中心假设，即 NP 与 T 细胞和 B 细胞 HIV-1 免疫原结合 将在粘膜组织中引起协同的细胞和体液免疫反应。完成时 拟议的研究中，我们将确定一种新的疫苗接种技术，可以诱导粘膜 T 和 B 细胞 针对 HIV-1 的反应。这些研究将加速艾滋病毒疫苗的开发并推进我们的研究 对疫苗输送系统和粘膜免疫之间关系的基本了解。

Abstract Human immunodeficiency virus (HIV) primarily enters the host and initiates infection through mucosal tissues. Therefore, a vaccination strategy that can elicit cellular and humoral immune responses in mucosal tissues is urgently needed. However, there is currently no approved adjuvant that can achieve robust levels of both T-cell and antibody responses in mucosal tissues. Therefore, there is a critical need for an alternative, effective, and safe strategy for mucosal vaccination. Our long-range goal is to develop vaccine delivery systems that can elicit protective immunity against HIV-1. Our objective here is to engineer nanoparticles for mucosal delivery of HIV-1 antigens and investigate their impact on elicitation of systemic and mucosal immune responses. To that end, we have developed a new lipid-based nanoparticle (NP) system that can elicit strong cytotoxic CD8+ T lymphocyte (CTL) responses with subunit protein antigens. We show that these new vaccine NPs promote antigen delivery to antigen-presenting cells in vivo, generate CTLs that disseminate to mucosal tissues, including cervicovaginal and gastrointestinal tracts, and protect animals against viral infection. We also show that NPs induce significantly higher antibody titers, lasting > 400 days in mice with greater avidity, durability, and breath, compared with conventional adjuvants on the market (e.g. alum or Montanide). Based on these preliminary data, we propose to develop a new nanoformulation-based strategy for mucosal immunization against HIV-1. We will test our central hypothesis that NPs incorporated with T and B-cell HIV-1 immunogens will elicit concerted cellular and humoral immune responses in mucosal tissues. At the completion of the proposed studies, we will have identified a new vaccination technology that can induce mucosal T and B cell responses against HIV-1. These studies will accelerate HIV vaccine development and advance our fundamental understanding of the relationship between vaccine delivery systems and mucosal immunity.