Restriction of HIV-1 transmission by type 1 interferons

1 型干扰素限制 HIV-1 传播

• 批准号: 9275913
• 负责人: Beatrice H Hahn
• 金额: $ 59.71万
• 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: 2014-06-06 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275913
• 关键词: APOCEC3G gene; Affect; Antiviral Agents; Automobile Driving; Blood specimen; Bone Marrow; CD34 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Consensus; Data; Defense Mechanisms; Development; Engraftment; Exhibits; Gene Expression; Genes; Goals; HIV-1; Host Defense; Host Defense Mechanism; Impairment; Infection; Interferons; Intervention; Lead; Liver; Macaca; Maps; Measures; Mediating; Methods; Modeling; Modification; Molecular Cloning; Mucous Membrane; Mus; Nucleotides; Patients; Pattern; Phenotype; Property; Prospective Studies; Resistance; Role; Site; Site-Directed Mutagenesis; Small Interfering RNA; Systemic infection; Testing; Therapeutic; Thymus Gland; Vaccines; Vagina; Variant; Viral; Viral Drug Resistance; Virus; Virus Replication; base; combat; cytokine; design; expression vector; fitness; gene complementation; genetic information; in vivo; interferon alpha-1; microbicide; mucosal site; novel virus; overexpression; pressure; prevent; prophylactic; protein expression; public health relevance; response; transmission process; virus genetics

DESCRIPTION (provided by applicant): Mucosal infection with HIV-1 is characterized by the rapid induction of type 1 interferons (IFNs) at the initial sites of entry. However, the extent to which these cytokines control HIV-1 replication during the earliest stages of infection and their contribution to the transmission bottleneck are not understood. We recently discovered that transmitted founder (TF) viruses that have crossed the mucosa and initiated a productive systemic infection are significantly more resistant to the antiviral effects of type 1 IFNs than viruses that predominate during chronic HIV-1 infection (1, 2). These findings strongly suggest that antiviral genes up-regulated by type 1 IFNs during the earliest stages of infection 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 t capitalize on this observation by identifying the IFN-stimulated antiviral genes that counteract HIV-1 replication at the site of entry and by determining whether these effector mechanisms can be exploited for the design of new prophylactic and therapeutic strategies to combat HIV-1. Our working hypothesis is that understanding the host antiviral effector mechanisms which control HIV-1 during the earliest stages of infection will lead to new interventions that are capable of impairing virus acquisition and initial spread, and may also have therapeutic utility. We have established a novel virus-based approach that will allow us to dissect the contribution of type 1 IFNs to the early "anti-viral state" in the mucosa and characterize 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 impact of type 1 IFN resistance on HIV-1 transmission fitness. 2. To examine the potential of different type 1 IFN subtypes to restrict HIV-1 transmission. 3. To map the viral determinants that confer type 1 IFN resistance on transmitted founder viruses. 4. To identify the IFN-stimulated genes (ISGs) that exert selective pressure on HIV-1 during the earliest stages of infection. We expect these studies to reveal whether type 1 IFNs have the capacity to extinguish foci of virus replication at the mucosal site of entry and to identify the particular interferon-stimulated genes (ISGs) that mediate this important early antiviral activity.

描述（由申请方提供）：HIV-1粘液瘤感染的特征是在初始进入部位快速诱导1型干扰素（IFN）。然而，这些细胞因子在感染的最早阶段控制HIV-1复制的程度及其对传播瓶颈的贡献尚不清楚。我们最近发现，已穿过粘膜并引发生产性全身感染的传播创始者（TF）病毒对1型IFN的抗病毒作用的抵抗力明显高于慢性HIV-1感染期间占主导地位的病毒（1，2）。这些研究结果强烈表明，1型干扰素在感染的最早阶段上调的抗病毒基因对传播的HIV-1库施加了显着的选择性压力，导致建立系统性感染的变异，相对干扰素耐药。在本申请中，我们建议利用这一观察结果，确定干扰素刺激的抗病毒基因，抵消HIV-1复制的网站进入，并确定这些效应机制是否可以利用新的预防和治疗策略，以打击HIV-1的设计。我们的工作假设是，了解在感染的最早阶段控制HIV-1的宿主抗病毒效应机制，将导致新的干预措施，能够削弱病毒的获得和最初的传播，也可能有治疗效用。我们已经建立了一种新的病毒为基础的方法，将使我们能够解剖的贡献1型干扰素的早期“抗病毒状态”的粘膜和表征特定的干扰素刺激基因（ISGs）参与，沿着TF病毒决定簇，赋予其活性的抵抗力。具体目标是：1。量化1型干扰素耐药对HIV-1传播适应度的影响。2.研究不同的1型干扰素亚型限制HIV-1传播的潜力。3.绘制赋予传播的创始者病毒1型IFN抗性的病毒决定簇。4.鉴定在感染早期阶段对HIV-1产生选择性压力的IFN刺激基因（ISG）。我们希望这些研究能够揭示1型干扰素是否有能力消灭病毒复制病灶的粘膜网站的入口，并确定特定的干扰素刺激的基因（ISGs），介导这一重要的早期抗病毒活性。