MODULATING HIV-IMMUNITY WITH DENDRITIC CELLS

描述（由申请人提供）：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）在免疫应答的启动和调节中发挥关键作用。树突状细胞是典型的抗原呈递细胞（APC），战略性地位于组织中，在那里它们可以感知入侵的病原体，并将病原体相关信息传递给淋巴细胞，从而启动适应性免疫和免疫记忆。然而，在HIV感染期间，宿主只能发起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表明，利用活病毒载体的“prime-boost”疫苗策略能够诱导T细胞免疫，并控制病毒复制。然而，使用活病毒载体引起了对潜在副作用的担忧。因此，迫切需要设计新的和安全的策略来增强艾滋病毒免疫。在这项拨款提案中，我们将测试一种策略，该策略可以在体内增强dc的数量和功能，从而在预防性和治疗性疫苗设置中在非人类灵长类动物中引发强大的抗病毒免疫。为了实现这一目标，我们建议利用DC生长因子、Fit-3配体（FL）和DC激活剂（CpG DNA）的卓越能力。已知FL可以增加小鼠和人类的DC数。CpG DNA触发在浆细胞样DC中表达的toll样受体-9 (TLR-9)，并诱导大量抗病毒细胞因子干扰素（IFN α）的产生。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引发更高水平的抗病毒免疫反应。这些问题将在以下具体目标中得到解决：目标1：确定最佳DC扩增和激活的参数，[用FL+CpG]，这是在健康猕猴中引发强大抗原特异性免疫所必需的。目的2：确定fl诱导DC扩增，随后CpG-DNA诱导DC在体内活化，是否能增强猕猴对SIV的预防性疫苗免疫。目的3：确定fl诱导的DC扩增，随后CpG-DNA诱导的DC在体内激活，是否能增强慢性SIV感染猕猴的治疗性疫苗免疫。如果取得成功，这一战略很可能在今后大大推动设计有效的人体艾滋病毒/艾滋病疫苗。

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.