Elicitation of mucosal immune responses against HIV

摘要 人类免疫缺陷病毒(HIV)主要通过粘膜组织进入宿主并引发感染。 因此，一种可以在粘膜组织中诱导细胞和体液免疫反应的疫苗接种策略是 急需之物。然而，目前还没有批准的佐剂可以达到这两种T细胞的强劲水平 以及粘膜组织中的抗体反应。因此，迫切需要一种替代、有效和 粘膜疫苗接种的安全策略。我们的长期目标是开发能够 诱导对HIV-1的保护性免疫。我们的目标是设计用于粘膜递送的纳米颗粒 并研究其对系统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，可以诱导出强大的细胞毒性CD8 T淋巴细胞(CTL)对亚单位蛋白抗原的反应。我们发现这些新的疫苗NPs能促进 将抗原递送到体内的抗原提呈细胞，产生CTL并传播到粘膜组织， 包括宫颈、阴道和胃肠道，并保护动物免受病毒感染。我们还展示了 NPs能显著提高小鼠的抗体效价，可持续400天，具有更强的亲和力，耐受性， 与市面上的常规佐剂(如明矾或蒙太尼)相比，这些助剂具有更强的抗氧化性和呼吸功能。基于这些 初步数据，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。我们将验证我们的中心假设，即NPs与T细胞和B细胞HIV-1免疫原结合 将在粘膜组织中引发协同的细胞和体液免疫反应。在完成 提出的研究，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 对HIV-1的反应。这些研究将加速艾滋病毒疫苗的开发，并推动我们的 对疫苗递送系统和粘膜免疫之间的关系有基本的了解。

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.