MODULATING HIV-IMMUNITY WITH DENDRITIC CELLS

描述(申请人提供)：人类免疫缺陷病毒(HIV)通过感染协调抗病毒免疫的免疫系统细胞来破坏宿主防御。在这些细胞类型中，树突状细胞(DC)在免疫反应的启动和调节中起着关键作用。树突状细胞(DC)是典型的抗原提呈细胞(APC)，位于组织中，可以感知入侵的病原体，并将病原体相关的信息传递给淋巴细胞，从而启动获得性免疫和免疫记忆。然而，在HIV感染期间，宿主只能发动微弱和短暂的免疫反应，导致慢性感染的建立。非人灵长类动物感染模型显示，利用活病毒载体的“主-增强”疫苗策略能够诱导T细胞免疫，并控制病毒复制。然而，活病毒载体的使用引发了人们对潜在不利影响的担忧。因此，迫切需要制定新的、安全的战略来加强艾滋病毒免疫。在这项拨款提案中，我们将测试一种在体内增强DC数量和功能的策略，以在预防和治疗性疫苗环境中在非人类灵长类动物中诱导强大的抗病毒免疫。为了实现这一目标，我们建议开发DC生长因子、FIT-3配体(FL)和DC激活剂(CpG DNA)的非凡能力。众所周知，FL可以扩大小鼠和人类的DC数量。CpG DNA可激活血浆细胞样树突状细胞表达的Toll样受体-9(TLR-9)，并诱导产生大量的抗病毒细胞因子干扰素(IFN-α)。我们假设，在DNA疫苗的背景下，FL和CpG DNA的结合将在预防和治疗环境中诱导抗病毒免疫反应水平的提高。这些问题将在以下具体目标中解决：目标1：确定在健康猕猴中诱导强大的抗原特异性免疫所必需的最佳DC扩增和激活的参数[FL+CpG]。目的：研究FL诱导的DC扩增和CpG-DNA在体内诱导的DC激活是否能增强猕猴对SIV的预防性疫苗免疫。目的：研究FL诱导的DC扩增和CpG-DNA在体内诱导的DC激活是否能增强SIV慢性感染猕猴的治疗性疫苗免疫。如果成功，这样的战略可能会极大地推动未来针对人类艾滋病毒/艾滋病的有效疫苗的设计。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) breaks down host defenses, by infecting cells of the immune system that orchestrate anti-viral immunity. Among these cell types, dendritic cells (DCs) perform critical functions in the initiation, and regulation of immune responses. DCs are the quintessential antigen-presenting cells (APC), and are strategically located in tissues, where they can sense invading pathogens, and convey pathogen-related information to lymphocytes, thus initiating adaptive immunity, and immune memory. However, during HIV infection, the host is able to mount only a weak and transient immune response, resulting in the establishment of chronic infection. Non-human primate models of infection have revealed that "prime-boost" vaccine strategies that utilize live viral vectors are capable of inducing T cell immunity, and controlling viral replication. However, the use of live viral vectors raises concerns about potential adverse effects. Therefore, there is an urgent need to devise novel and safe strategies to augment HIV-immunity. In this grant proposal we will test a strategy, which enhances the numbers and functions of DCs, in vivo to elicit robust anti-viral immunity in non-human primates, in both prophylactic and therapeutic vaccine settings. To achieve this goal, we propose to exploit the remarkable abilities of a DC growth factor, Fit-3 ligand (FL), and a DC activator (CpG DNA). FL is known to expand DC numbers in both mice and humans. CpG DNA triggers toll-like receptor-9 (TLR-9) expressed in plasmacytoid DC, and induces the production of copious amounts of the antiviral cytokine, interferon (IFN alpha). We hypothesize that the combination of both FL and CpG DNA in the context of DNA vaccines will elicit enhanced levels of anti-viral immune responses in both prophylactic and therapeutic settings. These issues will be addressed in the following specific aims: Aim 1: To determine the parameters for optimal DC expansion and activation, [with FL+CpG], necessary to elicit robust antigen-specific immunity in healthy macaques. Aim 2: To determine whether FL-induced DC expansion, followed by CpG-DNA induced DC activation in vivo, enhances prophylactic vaccine immunity to SIV in macaques. Aim 3: To determine whether FL-induced DC expansion, followed by CpG-DNA induced DC activation in vivo, enhances therapeutic vaccine immunity in macaques chronically infected with SIV. If successful, such a strategy will likely greatly advance the design of effective vaccines against HIV/AIDS in humans in the future.