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

• 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
• 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

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机制，在感染的最早阶段控制进入位点的 HIV-1 复制，可能有助于开发有效的艾滋病疫苗。我们的实验室在实现这一目标方面取得了重大进展，证明已穿过粘膜并引发有效全身感染的传播创始人 (TF) 病毒对 1 型干扰素 (IFN) 的抗病毒作用的抵抗力比慢性期占主导地位的病毒要强得多。感染（Parrish 等人，PNAS，2013；Fenton-May 等人提交）。这些发现表明，被 1 型 IFN 上调的抗病毒基因对传播的 HIV-1 池产生显着的选择性压力，导致相对 IFN 抵抗的变异体建立全身感染。在此应用中，我们建议通过鉴定 IFN 刺激的抗病毒药物来利用这一发现 基因在进入位点抵抗 HIV-1 复制，并确定这些新发现的效应机制是否可以用于疫苗设计。我们的工作假设是，了解在感染的最早阶段控制 HIV-1 的宿主效应机制将导致能够削弱病毒获得和初始传播的新干预措施。我们建立了一种基于病毒的新型方法，通过表征所涉及的特定干扰素刺激基因（ISG）以及 TF 病毒决定因素，可以剖析导致粘膜早期“抗病毒状态”的因素。赋予对其活动的抵抗力。具体目标是： 1. 量化 1 型 IFN 抗性对 HIV-1 传播适应性的贡献。 2. 绘制赋予传播的始祖病毒 1 型 IFN 抗性的病毒决定因素。 3. 鉴定在感染早期阶段对 HIV-1 施加抗病毒压力的 IFN 刺激基因 (ISG)。 4. 比较不同疫苗接种方案诱导抗病毒 ISG 的能力 在早期 HIV-1 控制中发挥重要作用。我们期望这些研究能够为不同疫苗接种策略的能力提供重要的新见解，以诱导抗病毒效应机制，控制传播部位或附近的 HIV-1 复制，在病毒最脆弱的暴露后数小时和数天内发挥作用。 。