Nonhuman Primate Core

非人类灵长类核心

• 批准号: 10460075
• 负责人: Francois J Villinger
• 金额: $ 53.24万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460075
• 关键词: Acute; Address; Adult; Animals; Attention; Autopsy; Bar Codes; Biological Markers; Biopsy; Blood; CCR5 gene; Cell Lineage; Cells; Clinic; Collection; Data; Dose; Evolution; Female; Future; Goals; HIV; HIV Infections; HIV-1; Human; Image; Imaging Techniques; Imaging technology; Immune; ImmunoPET; Immunologic Deficiency Syndromes; In Vitro; Infection; Interruption; Intervention; Investigation; Lentivirus; Lymphocyte; Lymphoid Tissue; Macaca mulatta; Maintenance; Maintenance Therapy; Maps; Measures; Microscopy; Modeling; Molecular; Monitor; Mucous Membrane; Myelogenous; Outcome; PET/CT scan; Patients; Penetration; Pharmaceutical Preparations; Phase; Plasma; Primates; Property; Research; Residual state; Resources; Role; SIV; Sampling; Series; Signal Transduction; Site; Source; Structure; T-Lymphocyte; Techniques; Time; Tissues; Tryptase; Viral; Viral Load result; Viral Physiology; Viral Proteins; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Replication; Work; X-Ray Computed Tomography; acute infection; antiretroviral therapy; cell type; experience; image guided; immunological intervention; in vivo; macrophage; mast cell; nonhuman primate; novel strategies; programs; simian human immunodeficiency virus; specific biomarkers; therapy design; tool; treatment duration; viral detection; viral rebound

A major barrier to HIV cure is the persistence of HIV-1 infected cells that constitute the viral reservoir which even after prolonged combined antiretroviral therapy (cART), fuels a consistent and rapid rebound if viral replication following cART interruption. This has unfortunately been true even for patients initiated on ART during acute infection. Thus, long-term persistent HIV reservoirs are seeded rapidly post infection, and our team and others have confirmed this finding in 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 cART, be it due to poor drug penetration, drug metabolization, or sanctuaries with limited antiviral immune contribution. Preliminary data from our ongoing reservoir investigations in the simian immunodeficiency infection of rhesus macaques with ART initiated less than 7 days post infection have led to unexpected findings: 1) we were able to see SIV expand and colonize the entire host for >1 week post cART initiation using immunoPET/CT monitoring, with signal decreasing thereafter; 2) Even after 6-8 months of cART, immunoPET/CT was sensitive enough to detect residual viral (protein) signal in tissues in spite of undetectable viremia in the blood; upon ART interruption, viral signals rebounded as early as 4 days post cART interruption (ATI) but also 2 weeks before detection of virus in plasma; analysis of the tissues and cells fueling this initial rebound surprisingly showed a paucity if not absence of T cells, but predominantly myeloid type cells, among which, many appeared positive for the mast cell specific tryptase biomarker. While our team had documented the ability of developing mast cells to be susceptible to HIV and SIV infection in vitro in the past, this was the first clear evidence that mast cells may contribute at the very least to the very early seeded SIV reservoir. In this application, we propose to quantify and map the reservoir formation in the context of cART initiation at 6 weeks post infection, as more representative of the human clinic, using a series of state of the art imaging guided collection techniques allowing for detailed cellular and viral analyses of the reservoirs obtained at various times of cART and early ATI. Next we propose to address the functional viral reservoir following prolonged cART with and without immune interventions designed to allow for transient viral replication, and finally, investigate the role of such interventions on the reservoir dynamic and composition upon ATI, in efforts to articulate novel strategies to silence viral reservoirs in the future

HIV治愈的一个主要障碍是HIV-1感染细胞的持续存在，这些细胞构成了病毒库， 在长期联合抗逆转录病毒治疗（cART）后，如果病毒复制， cART中断后。不幸的是，即使对于在急性期开始接受ART的患者来说，情况也是如此 感染因此，长期持续的HIV宿主在感染后迅速播种，我们的团队和其他人 在非人灵长类HIV模型中证实了这一发现。此外，来自几个小组的数据和 我们的研究强烈地表明，尽管存在病毒复制，但在各种淋巴组织中， 高活性cART，无论是由于药物渗透性差、药物代谢或抗病毒药物有限的避难所 免疫贡献。我们正在进行的猴免疫缺陷病毒储库调查的初步数据 在感染后7天内开始用ART感染恒河猴导致了意想不到的发现： 1)我们能够看到SIV在cART启动后>1周内扩增并定殖于整个宿主， 免疫PET/CT监测，此后信号降低; 2）即使在6-8个月的cART后， 免疫PET/CT灵敏度足以检测组织中残留的病毒（蛋白质）信号， 血液中存在病毒血症; ART中断后，病毒信号早在cART中断后4天反弹 (ATI)而且在血浆中检测到病毒前2周;分析组织和细胞， 令人惊讶的是，反弹显示缺乏T细胞，但主要是骨髓型细胞， 其中许多对肥大细胞特异性类胰蛋白酶生物标志物呈阳性。虽然我们的团队记录了 在过去，肥大细胞在体外对HIV和SIV感染易感的能力，这是第一个 明确的证据表明，肥大细胞可能至少有助于非常早期接种的SIV水库。在这 应用中，我们建议量化和映射储层形成的背景下，cART启动6周 感染后，作为更能代表人类临床的，使用一系列最先进的成像引导， 收集技术允许在不同时间获得的储库的详细细胞和病毒分析 CART和早期ATI。接下来，我们建议在延长的cART后， 没有免疫干预，旨在允许短暂的病毒复制，最后，调查的作用， 在努力阐明新的战略时， 在未来让病毒宿主沉默