Engineering antiviral innate immunity for safe and effective microbicides

设计抗病毒先天免疫以获得安全有效的杀菌剂

基本信息

批准号：
8511550
负责人：
Hong Shen
金额：
$ 32.24万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511550
关键词：
Address Agonist Antiviral Agents Autoimmunity Cell Culture Techniques Cells Chemicals Confidence Intervals Development Economic Burden Effectiveness Engineering Epithelial Epithelial Cells Exposure to Female genitalia Genital system Glycolic-Lactic Acid Polyester HIV HIV Infections HIV-1 Human Herpesvirus 2 Immune Immunity Infection Infection Control Inflammatory Inflammatory Response Interferon Type I Interferons Knowledge Lesion Lymphoid Measures Mediating Natural Immunity Oligonucleotides Pattern recognition receptor Peptides Phase Poly C Poly I-C Prevention strategy Reporting Risk Estimate Risk Factors Sexually Transmitted Agents Sexually Transmitted Diseases Shapes Site Small Interfering RNA System TLR3 gene Toll-like receptors Toxic effect Translations Vaccines Viral Viral Proteins Virus Virus Diseases Virus Receptors Virus Replication adaptive immunity base cell type controlled release cytokine design effective intervention falls genital herpes health economics microbicide mouse model nanoparticle response targeted delivery transmission process

项目摘要

Title: Engineering antiviral innate immunity for safe and effective microbicides HIV infections afflict millions of people and cause tremendous health and economic burdens. One of the major risk factors for HIV-1 transmission is the pre-existing infections caused by sexually transmitted agents such as herpes simplex virus type 2 (HSV-2). Therefore, a rational prevention strategy to halt HIV spread is to target HSV-2 infection and control its spread. In the absence of vaccines against HSV-2, a more practical and effective intervention for HSV-2 is the utilization of microbicides. A promising microbicidal approach is to potentiate antiviral innate immunity effective against a broad range of viruses at the site of viral encounters. The toll-like receptor (TLR)-based innate immunity have been shown to be crucial in initiating a cascade of antiviral activities mediated by type I interferons (IFNs). Both TLR3 and TLR9 agonists, polyinosinic:polycytidylic acid (poly IC) and CpG oligonucleotides (ODNs), are effective in protection against HSV-2 infections. However, undesirable inflammatory responses and autoimmunity accompanying the non-specific stimulation of TLRs are of major concern, which could severely limit the use of TLR agonists as microbicides. Thus, the key to developing TLR agonists as microbicides is to target them to relevant cell types at the potential sites of viral exposure and to elicit IFN responses in a regulated fashion. We propose to develop localized, controlled-release, and cell-targeted delivery systems to regulate the stimulation of TLR-based innate antiviral immunity. In the R21 Phase, three aims will be accomplished: Aim 1: to design and characterize cell-targeted delivery systems based on poly (lactide-co-glycolide) (PLGA) nanoparticles to specifically and locally target pDCs and epithelial cells with TLR agonists; Aim 2: to evaluate the effectiveness against genital HSV-2 infections by locally and selectively targeting CpG ODNs and/or poly ICs to pDCs and epithelial cells with cell-targeted nanoparticles; Aim 3: to evaluate toxicityby locally and selectively targeting CpG ODNs and/or poly ICs to pDCs and epithelial cells with cell-targeted nanoparticles. Built upon the results from the R21 phase, in the R33 phase, we will accomplish: Aim 4: to design and characterize delivery systems for sustained release of TLR agonists; Aim 5: to evaluate the effectiveness against genital HSV-2 infection and toxicity by localized, sustained-release and cell-targeted nanoparticles loaded with CpG ODNs and/or poly IC; Aim 6: to evaluate the adaptive immunity against genital HSV-2 infection mediated by localized, sustained-release and cell targeted nanoparticles loaded with CpG ODNs and/or poly IC. This application will enable the translation of TLR-based antiviral innate immunity to effective and safe microbicides.

标题：工程抗病毒先天免疫，以实现安全有效的微生物艾滋病毒感染困扰着数百万人，并造成巨大的健康和经济负担。 HIV-1传播的主要危险因素之一是性感染。传输剂，例如单纯疱疹病毒2型（HSV-2）。因此，有理预防阻止HIV传播的策略是针对HSV-2感染并控制其传播。在没有针对HSV-2的疫苗，对HSV-2的更实际和更有效的干预是利用微生物。一种有希望的杀生方法是增强抗病毒先天免疫有效在病毒相遇部位与广泛的病毒相比。基于收费的受体（TLR）先天免疫已被证明对于启动一系列抗病毒活性至关重要通过类型I干扰素（IFNS）。 TLR3和TLR9激动剂，聚精素：聚囊酸（poly IC）和CpG寡核苷酸（ODN）可有效防止HSV-2感染。然而，伴随着非特异性刺激的不良炎症反应和自身免疫性 TLR是主要关注的问题，这可能严重限制了TLR激动剂作为生体的使用。因此，开发TLR激动剂作为菌皮剂的关键是将它们靶向相关的细胞类型病毒暴露的潜在部位并以受管制的方式引起IFN反应。我们建议开发局部，受控的释放和细胞靶向输送系统，以调节刺激基于TLR的先天抗病毒免疫。在R21阶段，将实现三个目标：目标1：设计和表征基于聚（乳酸 - 糖糖苷）（PLGA）的细胞靶向输送系统（PLGA）纳米颗粒具有特异性和局部用TLR激动剂靶向PDC和上皮细胞；目标2：到通过局部和选择性靶向CPG来评估针对生殖器HSV-2感染的有效性 odn和/或poly ICS与细胞靶向纳米颗粒的PDC和上皮细胞；目标3：评估毒性通过本地和有选择性地靶向CpG ODN和/或多IC 细胞靶向的纳米颗粒。基于R21阶段的结果，在R33阶段，我们将完成：目标4：设计和表征持续释放TLR的输送系统激动剂；目标5：评估对生殖器HSV-2感染和毒性的有效性局部，持续释放和靶向细胞的纳米颗粒，上面装有CpG ODN和/或Poly IC；目标6：评估对局部，局部介导的生殖器HSV-2感染的适应性免疫力持续释放和靶向细胞的纳米颗粒，带有CpG ODN和/或Poly IC。这应用将使基于TLR的抗病毒先天免疫转换为有效和安全微生物。