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治疗的主要障碍是HIV-1感染细胞的持续性，该细胞构成病毒储存库在长时间的抗逆转录病毒疗法（CART）延长后，如果病毒复制，则可以迅速反弹在购物车中断之后。不幸的是，即使对于在急性期间发起艺术的患者也是如此感染。因此，长期持续的艾滋病毒水库被迅速在感染后播种，我们的团队和其他人在非人类的灵长类动物模型中证实了这一发现。此外，来自几个组的数据以及我们的强烈表明，尽管高度活跃的购物车，无论是由于药物渗透不良，药物代谢还是抗病毒有限的庇护所免疫贡献。我们正在进行的水库调查中的初步数据感染后少于7天的ART感染猕猴的感染导致了意外的发现： 1）我们能够看到SIV扩展和定居整个主机，以> 1周的启动后使用免疫集/CT监测，此后信号降低； 2）即使经过6-8个月的购物车，免疫集/CT足够敏感，可以检测组织中残留的病毒（蛋白质）信号，尽管无法检测到血液中的病毒血症；在艺术中断时，货车中断后4天就会反弹病毒信号（ATI），但在血浆中发现病毒之前的2周；分析燃料的组织和细胞反弹令人惊讶地显示出较弱的情况，即使不存在T细胞，但主要是髓样细胞，这对于肥大细胞特异性胰蛋白酶生物标志物似乎是阳性的。当我们的团队记录了过去，开发肥大细胞在体外易受HIV和SIV感染的能力，这是第一个明确的证据表明，肥大细胞可能至少对非常早期的SIV储层产生贡献。在这个应用，我们建议在6周的购物车启动下量化和映射储层形成感染后，作为人类诊所的更多代表，使用一系列最先进的成像状态收集技术允许在不同时间获得的储层的详细的细胞和病毒分析购物车和早期的Ati。接下来，我们建议在长时间的手推车上解决功能性病毒储层并且没有旨在允许瞬时病毒复制的免疫干预措施，最后研究角色在ATI上对储层动态和组成的这种干预措施，以阐明新型策略将来沉默病毒储量