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.

摘要 - 核心 B：非人类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。尽管 目前的抗逆转录病毒联合疗法能够将病毒复制抑制到可检测水平以下（50 拷贝数）在患者血浆中，停止 ART 几乎总是会导致病毒复发，即使是在患者中 ART 是在感染后早期开始的。这导致了休克和杀戮方法的制定 在 ART 的保护下使用潜伏期逆转剂激活并减少储库，尽管这样 迄今为止，在缺乏免疫治疗的情况下的方法尚未产生任何临床益处。然而，这些结果 明确表明，长期持续存在的艾滋病毒储存库在感染后迅速播种，正如所证实的那样 非人类灵长类动物艾滋病毒模型。此外，来自几个小组和我们的数据强烈表明，残留 尽管 ART 非常活跃，但病毒复制实际上在各种淋巴组织中持续进行，这是由于 药物渗透、转化或抗病毒免疫作用有限的庇护所。在这个应用程序中，我们 建议量化和绘制阴道感染和早期 ART 干预后早期储库形成的图谱， 使用一系列最先进的成像技术以及对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以下功能库问题 延长 ART 和 ART 中断，监测组织中残留病毒复制、早期病毒位点 反弹、活性储存库的细胞起源以及旨在增强抗病毒作用的免疫干预措施 导致抗病毒控制的反应。