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）：阐明在感染的早期阶段控制HIV-1进入位点复制的宿主先天抗病毒效应机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，证明通过粘膜传播的创始病毒（TF）与慢性感染期间占主导地位的病毒相比，对1型干扰素（ifn）的抗病毒作用具有更强的抵抗力（Parrish等人，PNAS, 2013； Fenton-May等人，提交）。这些发现表明，1型IFN上调的抗病毒基因对传播的HIV-1库施加了显著的选择压力，导致相对IFN耐药的变体建立全身性感染。在这个应用中，我们建议通过鉴定干扰素刺激的抗病毒药物来利用这一发现