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，可以在粘膜组织中引发细胞和体液免疫应答的疫苗接种策略是可行的。 迫切需要。然而，目前还没有批准的佐剂可以实现T细胞免疫和免疫调节的稳健水平。 和粘膜组织中的抗体应答。因此，迫切需要一种替代的，有效的， 粘膜接种的安全策略。我们的长期目标是开发疫苗输送系统， 引发针对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 研究HIV-1抗原对激发全身和粘膜免疫应答的影响。到 为此，我们开发了一种新的基于脂质的纳米颗粒（NP）系统，该系统可以引发强烈的细胞毒性CD 8 + 用亚单位蛋白抗原的T淋巴细胞（CTL）应答。我们表明，这些新的疫苗纳米颗粒促进 在体内将抗原递送至抗原呈递细胞，产生散布至粘膜组织的CTL， 包括子宫颈阴道和胃肠道，并保护动物免受病毒感染。我们还表明 NPs在小鼠中诱导显著更高的抗体滴度，持续> 400天，具有更大的亲和力，持久性， 和呼吸，与市场上的常规佐剂（例如明矾或Montanide）相比。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。我们将检验我们的中心假设，即纳米颗粒与T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应答。完成时 在拟议的研究中，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 对HIV-1的反应。这些研究将加速艾滋病毒疫苗的开发， 对疫苗输送系统和粘膜免疫之间关系的基本理解。

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.