Intra-Host Phylogeography and Population Dynamics of SIV in the Rhesus Macaque Model of NeuroAIDS

神经艾滋病恒河猴模型中 SIV 的宿主内系统发育地理学和种群动态

• 批准号: 9138283
• 负责人: Brittany Magalis
• 金额: $ 3.67万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-18 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138283
• 关键词: Acquired Immunodeficiency Syndrome; Advisory Committees; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Antiviral Agents; Automobile Driving; Biological Assay; Biological Markers; Biopsy; Blood - brain barrier anatomy; Blood Circulation; Blood specimen; Bone Marrow; Bone Marrow Cells; Brain; Brain Injuries; CD8-Positive T-Lymphocytes; Cells; Central Nervous System Diseases; Central Nervous System Infections; Characteristics; Chronic; Development; Disease; Disease Progression; Disease model; Drug Design; Drug Targeting; Encephalitis; Environment; Ethical Issues; Event; Evolution; Genes; HIV; HIV Envelope Protein gp120; HIV-1; HIV-associated neurocognitive disorder; Human; Immune; Immune system; In Vitro; Infection; Inflammation; Knowledge; Lead; Link; Lymphocyte Depletion; Lymphoid Tissue; Macaca; Macaca mulatta; Marrow; Measurement; Measures; Methods; Modeling; Monitor; Myelin Basic Proteins; Nerve Degeneration; Neuraxis; Neuropathogenesis; Onset of illness; Patients; Pattern; Peripheral; Peripheral Blood Mononuclear Cell; Permeability; Pharmaceutical Preparations; Phylogenetic Analysis; Plasma; Plasma Cells; Play; Population; Population Dynamics; Prevalence; Proteins; Qualifying; RNA Sequences; Research Personnel; Resolution; Resources; Role; SIV; Sampling; Satellite Viruses; Sequence Analysis; Shapes; Sorting - Cell Movement; Testing; Time; Tissue Sample; Tissues; Variant; Viral; Viral Proteins; Virus; Virus Diseases; Work; adaptive immunity; base; bone; career; effective therapy; experience; genomic RNA; human subject; in vivo; longitudinal analysis; migration; monocyte; nervous system disorder; neuroAIDS; neuropathology; neurotoxic; neurotrophic protein S100beta; neurotropic; neurotropic virus; peripheral blood; pre-doctoral; pressure; public health relevance; spatiotemporal; success; time use; trafficking; viral RNA

 DESCRIPTION (provided by applicant): Despite the introduction of highly active antiretroviral treatment (HAART), the prevalence of HIV-associated neurocognitive disorders (HAND) among HIV-1-infected patients has increased. Currently, there is no effective therapy for HAND; therefore, a better understanding of the viral evolutionary factors driving the emergence of neurovirulent strains during disease onset and progression is of pivotal importance for developing a mechanistic model of neuroAIDS and improvement of drug design strategies. The objectives of the current proposal are to identify and characterize spatiotemporal dynamics of viral evolution among peripheral and central nervous system (CNS) tissues and cell populations associated with the onset and progression of neuropathogenesis in two distinct rhesus macaque models of neuroAIDS. Eighteen total macaques were infected with a genetically characterized viral swarm, from which peripheral blood and tissue samples were collected over time and used for amplification of viral gp120 genomic RNA. High-resolution phylogeographic analyses will reveal spatial and temporal aspects of intra-host viral seeding of the brain linked to the onset of a neuropathogenic infection that have not yet been characterized because of ethical issues associated with tissue sampling in humans. Specific Aim 1 will investigate the migration (gene flow) of cell-free virus from plasma and cell-associated virus from lymphoid tissues and peripheral blood mononuclear cells (PBMCs) to the CNS during the course of infection via longitudinal PBMC/tissue sampling and brain biopsies of macaques with and without CD8+ lymphocyte depletion. Specific Aim 2 will measure biomarkers of encephalitis-associated brain injury over time in order to investigate the link between viral evolutionary and population dynamics observed in Specific Aim 1 and disease onset and progression. Ultimately, we will be able to identify the spatiotemporal patterns of brain infection and evolutionary signatures leading to the emergence of neurotropic and neurovirulent populations that could be used to predict and monitor disease progression. Equally important is the potential utilization of these findings in th development of drugs that target viral and/or infected immune cell populations associated with neuropathogenesis. Overall, we will undertake the most comprehensive analysis of longitudinal SIV sequences from a variety of tissues to date. The principle investigator associated with this project, Dr. Marco Salemi, has significant experience in phylogenetic analysis and has worked to cultivate a resource-rich environment critical for the success of this project as well as my pre doctoral career. In addition, we have assembled a unique and qualified interdisciplinary advisory committee to assist in oversight and progression of this study.