Nonhuman Primate Core

非人类灵长类核心

基本信息

批准号：
10666570
负责人：
Francois J Villinger
金额：
$ 51.8万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10666570
关键词：
Acute Address Adult Animals Articulation Attention Autopsy Bar Codes Binding Biological Markers Biopsy Blood CCR5 gene Cell Lineage Cells Clinic Collaborations 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 Macrophage Maintenance Maintenance Therapy Maps Measures Microscopy Modeling Molecular Monitor Mucous Membrane Myelogenous Outcome PET/CT scan Patients Penetration Pharmaceutical Preparations Phase Plasma Predisposition Primates Property Proteins Research Residual state Resources Role SIV Sampling Series Signal Transduction Site Source Structure T-Lymphocyte Techniques Tissues Tryptase Viral Viral Load result Viral Physiology 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 mast cell nonhuman primate novel strategies programs specific biomarkers therapy design tool treatment duration viral detection viral rebound

项目摘要

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构成病毒库的HIV-1感染细胞的持续存在，甚至长期联合抗逆转录病毒治疗 (cART) 后，如果病毒复制持续且快速反弹 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，长期持续存在的艾滋病毒储存库在感染后迅速传播，我们的团队和其他人已经在非人类灵长类动物艾滋病毒模型中证实了这一发现。此外，来自多个团体的数据我们强烈建议，尽管残余病毒复制实际上在各种淋巴组织中正在进行高活性的 cART，可能是由于药物渗透不良、药物代谢或抗病毒药物有限的避难所免疫贡献。我们正在进行的猿猴免疫缺陷病毒储存库研究的初步数据恒河猴在感染后 7 天以内开始接受 ART 感染，结果出现了意想不到的结果： 1) 我们能够看到 SIV 在 cART 启动后 1 周内扩张并定殖于整个宿主，使用免疫PET/CT监测，此后信号减弱； 2) 即使经过 6-8 个月的 cART，尽管无法检测到，但免疫PET/CT的灵敏度足以检测组织中残留的病毒（蛋白质）信号血液中的病毒血症； ART 中断后，病毒信号最早在 cART 中断后 4 天反弹 (ATI) 但也在血浆中检测到病毒之前 2 周；对促进这一初始过程的组织和细胞的分析令人惊讶的是，反弹显示 T 细胞即使不是不存在，也很少，但主要是骨髓型细胞。其中，许多人的肥大细胞特异性类胰蛋白酶生物标志物呈阳性。虽然我们的团队已经记录了过去在体外培养出肥大细胞易受HIV和SIV感染的能力，这是第一个明确的证据表明肥大细胞至少可能对非常早期接种的 SIV 储库做出贡献。在这个应用程序中，我们建议在 6 周时开始 cART 的情况下量化和绘制储库形成图感染后，作为更具有代表性的人类临床，使用了一系列最先进的影像引导收集技术允许对不同时间获得的储存库进行详细的细胞和病毒分析 cART 和早期 ATI。接下来，我们建议解决长期 cART 后的功能性病毒库问题并且没有旨在允许短暂病毒复制的免疫干预措施，最后，研究其作用对 ATI 上的储层动态和成分进行此类干预，努力阐明新策略消除未来的病毒储存库