Harnessing type 1 IFN-stimulated antiviral mechanisms for HIV vaccine design

利用 1 型 IFN 刺激的抗病毒机制进行 HIV 疫苗设计

基本信息

批准号：
8705846
负责人：
Beatrice H Hahn
金额：
$ 21.72万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8705846
关键词：
AIDS Vaccines Accounting Adjuvant Affect Antiviral Agents Automobile Driving Biological Bone Marrow CD34 gene CD4 Positive T Lymphocytes Cells Chronic Consensus DNA Data Defense Mechanisms Development Engraftment Evolution Exhibits Gene Silencing Genes Genetic HIV vaccine HIV-1 Host Defense Hour Human Infection Interferon Type I Interferons Intervention Laboratories Lead Libraries Liver Maps Memory Methods Modification Molecular Cloning Mucous Membrane Mus Mutation Nucleotides Pathway interactions Patients Play Property Proteins Regimen Relative (related person)Resistance Role Site Site-Directed Mutagenesis Small Interfering RNA Staging Systemic infection Systems Biology T cell response Testing Thymus Gland Up-Regulation Vaccination Vaccine Design Vaccines Variant Viral Viral Drug Resistance Viral Vector Virus Virus Replication Work base cell type fitness in vivo insight mouse model novel strategies novel virus overexpression pressure protective effect public health relevance response transcriptome sequencing transmission process vaccination strategy vaccine development

项目摘要

DESCRIPTION (provided by applicant): Elucidation of the host innate antiviral effector mechanisms that control HIV-1 replication at the site of entry during the earliest stages of infection could be instrumental for the development of an effective AIDS vaccine. Our laboratories have made significant progress toward this objective by demonstrating that transmitted founder (TF) viruses that have crossed the mucosa and initiated a productive systemic infection are considerably more resistant to the antiviral effects of type 1 interferons (IFNs) than viruses that predominate during chronic infection (Parrish et al., PNAS, 2013; Fenton-May et al., submitted). These findings suggest that antiviral genes up-regulated by type 1 IFNs exert significant selective pressure on the transmitted HIV-1 pool, resulting in the establishment of systemic infection by variants that are relatively IFN resistant. In this application, we propose to capitalize on this discovery by identifying the IFN-stimulated antiviral genes that counteract HIV-1 replication at the site of entry and by determining whether these newly-identified effector mechanisms can be harnessed for vaccine design. Our working hypothesis is that understanding the host effector mechanisms that control HIV-1 during the earliest stages of infection will lead to new interventions that are capable of impairing virus acquisition and initial spread. We have established a novel virus-based approach that will allow us to dissect the factors that contribute to the early "anti-viral state" in the mucosa by characterizing the particular interferon stimulated genes (ISGs) involved, along with the TF virus determinants that confer resistance to their activity. Specific Aims are: 1. To quantify the contribution of type 1 IFN resistance to HIV-1 transmission fitness. 2. To map the viral determinants that confer type 1 IFN resistance on transmitted founder viruses. 3. To identify the IFN-stimulated genes (ISGs) that exert antiviral pressure on HIV-1 during the earliest stages of infection. 4. To compare the ability of different vaccination regimes to induce antiviral ISGs that play an important role in early HIV-1 control. We expect these studies to provide important new insight into the capacity of different vaccination strategies to induce antiviral effector mechanisms that control HIV-1 replication at or near the site of transmission, acting in the hours and days immediately following exposure when the virus is most vulnerable.

描述（由申请人提供）：阐明宿主先天抗病毒效应器机制，这些机制在最早的感染阶段控制入境部位的HIV-1复制可能对开发有效的艾滋病疫苗可能有助于。我们的实验室通过证明越过粘膜并发起生产性全身感染的传播创始人（TF）病毒取得了重大进展，对1型干扰素（IFN）的抗病毒效应的耐药性比在慢性感染期间占主导地位的抗病毒效应（Parrish等人，pnas et al。，pnas，fent。这些发现表明，由1型IFN上调的抗病毒基因对传输的HIV-1池施加了显着的选择性压力，从而导致由相对抗性的变体建立了全身感染。在此应用程序中，我们建议通过识别IFN刺激的抗病毒来利用这一发现抵消进入现场的HIV-1复制的基因，并确定是否可以利用这些新识别的效应器机制进行疫苗设计。我们的工作假设是，了解在最早的感染阶段控制HIV-1的宿主效应器机制将导致新的干预措施，这些干预措施能够损害病毒的获取和初始扩散。我们已经建立了一种新型的基于病毒的方法，该方法将使我们能够通过表征涉及的特定干扰素刺激基因（ISGS）以及TF病毒决定因素来赋予其活性抵抗的TF病毒决定因素，从而剖析粘膜早期“抗病毒状态”的因素。具体目标是：1。量化1型IFN对HIV-1传输适应性的贡献。 2。绘制赋予1型IFN抗性的病毒决定因素对传播的创建者病毒的抗性。 3。确定在最早的感染阶段对HIV-1施加抗病毒压力的IFN刺激基因（ISGS）。 4。比较不同疫苗接种制度诱导抗病毒ISG的能力在早期HIV-1控制中起重要作用。我们希望这些研究能够对不同的疫苗接种策略的能力诱导抗病毒效应器机制的能力提供重要的新见解，以控制传播部位或附近的HIV-1复制，在病毒最脆弱的情况下，在暴露后的几个小时和几天起作用。