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Nonhuman Primate Core

非人类灵长类核心

基本信息

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
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/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

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HIV-1感染细胞的持续存在，这些细胞构成了病毒库