Non-Human Primate and Imaging Core

非人类灵长类动物和成像核心

• 批准号: 10224631
• 负责人: Francois J Villinger
• 金额: $ 46.14万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224631
• 关键词: Address; Adult; Anti-Retroviral Agents; Antiviral Agents; Antiviral Response; Bar Codes; Biopsy; Blood; Cell Lineage; Cells; Clinical; Collection; Combined Modality Therapy; Data; Exposure to; Female; Formulation; Goals; HIV; HIV Infections; HIV-1; Hour; Image; Imaging Techniques; Imaging technology; Immune; Immune response; ImmunoPET; Immunotherapeutic agent; Immunotherapy; Infection; Interruption; Intervention; Laboratories; Lymphoid; Lymphoid Tissue; Macaca mulatta; Maintenance; Maps; Modeling; Monitor; Mucous Membrane; Organ; Pathogenesis; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Plasma; Primates; Probability; Prophylactic treatment; Reporter; Residual state; SIV; Series; Shock; Site; Time; Tissues; Vagina; Viral; Viral Load result; Viral reservoir; Viremia; Virus; Virus Latency; Virus Replication; acute infection; base; fluorophore; immunological intervention; in vivo; mTOR inhibition; neutralizing antibody; nonhuman primate; novel; prevent; programs; rectal; therapy design; treatment duration; vaginal infection; viral rebound

Summary - Core B: Non-human Primate and Imaging Core A major barrier to HIV cure is the persistence of HIV-1 infected cells that constitute the viral reservoir. While current antiretroviral combination therapies are able to inhibit viral replication to below detectable levels (50 copies) in the plasma of patient, ART cessation almost invariably leads to viral resurgence even in patients for which ART was initiated early post infection. This has led to the formulation of Shock and Kill approaches to activate and reduce the reservoirs using latency reversing agents under the umbrella of ART, though such approach in the absence of immunotherapy has not had any clinical benefit thus far. However, these results clearly indicate that long-term persistent HIV reservoirs are seeded rapidly post infection as confirmed it the nonhuman primate model of HIV. In addition, data from several groups and ours strongly suggest that residual viral replication is actually ongoing in various lymphoid tissues in spite of highly active ART, be it due to poor drug penetration, conversion or sanctuaries with limited antiviral immune contribution. In this application, we propose to quantify and map the early reservoir formation after vaginal infection and early ART intervention, using a series of state of the art imaging techniques as well detailed cellular analyses of the reservoirs obtained at various times of ART initiation. Next we propose to address the functional reservoir following prolonged ART and ART interruption, monitoring residual viral replication in tissues, sites of early viral rebound, the cellular origin of the active reservoir and immune interventions designed to bolster antiviral responses leading to antiviral control.

总结-核心B：非人灵长类动物和成像核心 HIV治愈的一个主要障碍是构成病毒库的HIV-1感染细胞的持续存在。而 目前的抗逆转录病毒联合疗法能够将病毒复制抑制到低于可检测水平（50 拷贝），ART停止几乎总是导致病毒复苏，即使在患者中， ART是在感染后早期开始的。这导致了休克和杀死方法的制定， 在ART的保护伞下使用潜伏期逆转剂激活和减少储库，尽管这种 在没有免疫疗法的情况下，这种方法迄今为止没有任何临床益处。然而，这些结果 清楚地表明，长期持续的艾滋病毒储存库在感染后迅速播种， 非人灵长类动物艾滋病病毒模型。此外，来自几个小组和我们的数据强烈表明， 尽管ART高度活跃，但病毒复制实际上在各种淋巴组织中仍在进行，无论是由于不良的 药物渗透、转化或具有有限抗病毒免疫贡献的避难所。在本申请中，我们 建议量化和绘制阴道感染和早期ART干预后的早期储库形成， 使用一系列最先进的成像技术以及储层的详细细胞分析 在ART启动的不同时间获得。接下来，我们建议解决功能性水库， 延长ART和ART中断，监测组织中残留的病毒复制，早期病毒感染的部位， 反弹，活跃水库的细胞起源和旨在加强抗病毒的免疫干预 导致抗病毒控制的反应。