Chimeric SHIV VLP as an oral mucosal HIV vaccine

描述（由申请人提供）： 通过疫苗诱导粘膜HIV特异性免疫应答可能有助于有效控制HIV或SIV在这些部位的复制。然而，目前还没有有效的HIV粘膜疫苗。本发明旨在鉴定有效的口服免疫原，确定最佳的简单有效的免疫途径，并揭示该疫苗可诱导有效的粘膜免疫应答以保护免受粘膜病毒攻击的作用机制。我们已经开发并表征了嵌合CD 40配体/猴-人免疫缺陷病毒（CD 40 L/SHIV）病毒样颗粒（VLP），其具有抗原呈递细胞（APC）成熟信号CD 40 L。我们已经证明，这种嵌合的CD 40 L/SHIV VLP具有直接结合和激活口腔粘膜和局部引流淋巴结（LN）中的树突状细胞（DC）的能力。与已经有效的SHIV VLP疫苗相比，嵌合CD 40 L/SHIV VLP可以通过口腔粘膜下免疫途径诱导高达4倍的粘膜伊加应答和粘膜细胞毒性T淋巴细胞（CTL）应答。目前，没有一种VLP粘膜疫苗策略在非人灵长类动物模型中显示出保护性功效。基于这些令人兴奋的初步数据，我们提出了我们的中心假设，即口腔粘膜下注射具有APC成熟信号CD 40 L的嵌合CD 40 L/SHIV VLP将直接结合并激活口腔粘膜和局部引流淋巴结（LN）中的DC，从而启动强大而有效的全身和粘膜免疫，这将保护恒河猴中的SHIV SF 162 P3攻击。为了检验我们的假设，我们提出了以下具体目标：目标1：确定最佳mCD 40 L/SHIV VLP口腔粘膜下免疫方案并表征小鼠中的粘膜免疫应答;目标2：确定hCD 40 L/SHIV VLP口腔粘膜疫苗接种在非人灵长类动物模型中对病理性SHIVSF 162 P3攻击的免疫原性和保护作用;以及目标3。阐明hCD 40 L/SHIV VLP口腔粘膜下疫苗接种在小鼠和非人灵长类动物中诱导强烈粘膜免疫应答的机制。该项目代表了一种新的抗原和免疫途径的探索，目的是开发一种有效和安全的嵌合SHIV VLP口腔粘膜HIV疫苗。这项研究也将增加我们对口腔粘膜免疫的理解，这可能有助于未来的口腔粘膜疫苗设计。我们未来的目标是推动这一有前途的策略，为预防艾滋病的有效口腔粘膜疫苗的发展。

DESCRIPTION (provided by applicant): Induction of mucosal HIV-specific immune responses by vaccines may facilitate effective control of HIV or SIV replication at these sites. However, there is no effective HIV mucosal vaccine yet. This proposal is intend to identify effective orally administered immunogen, determine the optimal easy and effective immunization route, and uncover the mechanism of action whereby this vaccine can induce potent mucosal immune responses to protect from mucosal viral challenge. We have developed and characterized chimeric CD40 ligand/simian-human immunodeficiency (CD40L/SHIV) virus-like particles (VLPs) which possess the antigen presenting cell (APC) maturation signal CD40L. We have shown that this chimeric CD40L/SHIV VLPs has the ability to directly bind and activate dendritic cells (DC) in oral mucosa and local draining lymph nodes (LN). Compared with the already potent SHIV VLP vaccine, the chimeric CD40L/SHIV VLPs can induce as much as 4-fold higher mucosal IgA response and mucosal cytotoxic T lymphcytes (CTL) response via an oral sub-mucosal immunization route. At present, none of the VLP mucosal vaccine strategies have been shown to enact protective efficacy in nonhuman primate models. Based on these exciting preliminary data, we have developed our central hypothesis that oral submucosal injection of chimeric CD40L/SHIV VLPs, which possess the APC maturation signal CD40L, will directly bind and activate DCs in oral mucosa and local draining lymph nodes (LN), thereby initiating strong and effective systemic and mucosal immunity that will protect SHIV SF162P3 challenge in rhesus macaques. To test our hypothesis, we propose the following specific aims: Aim 1: Determine the optimal mCD40L/SHIV VLP oral sub-mucosal immunization regimen and characterizing mucosal immune responses in mice; Aim 2: Determine the immunogenicity and protective effect of hCD40L/SHIV VLP oral mucosal vaccination from pathological SHIVSF162P3 challenge in a non-human primate model; and Aim 3. Decipher the mechanism whereby hCD40L/SHIV VLP oral submucosal vaccination induces strong mucosal immune responses in mice and in non-human primates. The proposed project represents exploration of a novel antigen and immunization route for the purpose of developing an effective and safe chimeric SHIV VLP oral mucosal HIV vaccine. This study will also increase our understanding of oral mucosal immunity, which may contribute to future oral mucosal vaccine design. Our future goal is to move this promising strategy forward for an effective oral mucosal vaccine development for preventing AIDS.