Restriction of HIV-1 transmission by type 1 interferons

1 型干扰素限制 HIV-1 传播

• 批准号: 8786805
• 负责人: Beatrice H Hahn
• 金额: $ 63.05万
• 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/8786805
• 关键词: Affect; Antiviral Agents; Automobile Driving; Blood specimen; Bone Marrow; CD34 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Complement; Consensus; Data; Defense Mechanisms; Development; Engraftment; Exhibits; Gene Expression; Genes; Goals; HIV-1; Health; Host Defense; Host Defense Mechanism; Infection; Interferon Type I; Interferons; Intervention; Lead; Liver; Macaca; Maps; Measures; Mediating; Methods; Modeling; Modification; Molecular Cloning; Mucous Membrane; Mus; Nucleotides; Patients; Pattern; Phenotype; Property; Resistance; Role; Site; Site-Directed Mutagenesis; Staging; Systemic infection; Testing; Therapeutic; Thymus Gland; Vaccines; Variant; Viral; Viral Drug Resistance; Virus; Virus Replication; Work; base; combat; cytokine; design; expression vector; fitness; in vivo; microbicide; mucosal site; novel virus; overexpression; pressure; prevent; prophylactic; protein expression; 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（由申请人提供）：HIV-1 粘膜感染的特点是在初始进入位点快速诱导 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，与慢性 HIV-1 感染期间占主导地位的病毒相比，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 IFN 的抗病毒作用的抵抗力明显更强 (1, 2)。这些发现强烈表明，在感染的最早阶段，1型干扰素上调的抗病毒基因对传播的HIV-1池产生了显着的选择性压力，导致对干扰素相对具有抵抗力的变异体引起全身感染。在本申请中，我们建议利用这一观察结果，识别干扰素刺激的抗病毒基因，这些基因在进入位点抵消HIV-1的复制，并确定这些效应机制是否可以用于设计新的预防和治疗策略来对抗HIV-1。我们的工作假设是，了解在感染早期阶段控制 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获得和初始传播，并且也可能具有治疗效用。我们建立了一种基于病毒的新型方法，使我们能够剖析 1 型干扰素对粘膜早期“抗病毒状态”的贡献，并表征所涉及的特定干扰素刺激基因 (ISG)，以及赋予其活性抗性的 TF 病毒决定簇。具体目标是： 1. 量化 1 型 IFN 耐药性对 HIV-1 传播适应性的影响。 2. 检查不同 1 型 IFN 亚型限制 HIV-1 传播的潜力。 3. 绘制赋予传播的始祖病毒 1 型 IFN 抗性的病毒决定因素。 4. 鉴定在感染早期阶段对 HIV-1 施加选择性压力的 IFN 刺激基因 (ISG)。我们期望这些研究能够揭示1型干扰素是否有能力消灭进入粘膜部位的病毒复制灶，并鉴定介导这种重要的早期抗病毒活性的特定干扰素刺激基因（ISG）。