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
基本信息
- 批准号:9138283
- 负责人:
- 金额:$ 3.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Acquired Immunodeficiency SyndromeAdvisory CommitteesAnti-Inflammatory AgentsAnti-Retroviral AgentsAnti-inflammatoryAntiviral AgentsAutomobile DrivingBiological AssayBiological MarkersBiopsyBlood - brain barrier anatomyBlood CirculationBlood specimenBone MarrowBone Marrow CellsBrainBrain InjuriesCD8-Positive T-LymphocytesCellsCentral Nervous System DiseasesCentral Nervous System InfectionsCharacteristicsChronicDevelopmentDiseaseDisease ProgressionDisease modelDrug DesignDrug TargetingEncephalitisEnvironmentEthical IssuesEventEvolutionGenesHIVHIV Envelope Protein gp120HIV-1HIV-associated neurocognitive disorderHumanImmuneImmune systemIn VitroInfectionInflammationKnowledgeLeadLinkLymphocyte DepletionLymphoid TissueMacacaMacaca mulattaMarrowMeasurementMeasuresMethodsModelingMonitorMyelin Basic ProteinsNerve DegenerationNeuraxisNeuropathogenesisOnset of illnessPatientsPatternPeripheralPeripheral Blood Mononuclear CellPermeabilityPharmaceutical PreparationsPhylogenetic AnalysisPlasmaPlasma CellsPlayPopulationPopulation DynamicsPrevalenceProteinsQualifyingRNA SequencesResearch PersonnelResolutionResourcesRoleSIVSamplingSatellite VirusesSequence AnalysisShapesSorting - Cell MovementTestingTimeTissue SampleTissuesVariantViralViral ProteinsVirusVirus DiseasesWorkadaptive immunitybasebonecareereffective therapyexperiencegenomic RNAhuman subjectin vivolongitudinal analysismigrationmonocytenervous system disorderneuroAIDSneuropathologyneurotoxicneurotrophic protein S100betaneurotropicneurotropic virusperipheral bloodpre-doctoralpressurepublic health relevancespatiotemporalsuccesstime usetraffickingviral RNA
项目摘要
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.
描述(申请人提供):尽管引入了高效抗逆转录病毒治疗(HAART),但 HIV-1 感染患者中 HIV 相关神经认知障碍(HAND)的患病率有所增加,目前尚无有效的治疗方法。因此,更好地了解在疾病发作和进展过程中驱动神经毒株出现的病毒进化因素对于开发神经艾滋病的机制模型和改进药物设计策略至关重要。提案旨在确定和表征与两种不同的神经艾滋病恒河猴模型中神经发病机制的发生和进展相关的外周和中枢神经系统(CNS)组织和细胞群中病毒进化的时空动态。总共十八只猕猴感染了具有遗传特征的病毒。病毒群,随着时间的推移从其中收集外周血和组织样本并用于扩增病毒 gp120 基因组 RNA 的高分辨率系统发育地理学分析将揭示病毒群的空间和时间方面。大脑内宿主病毒播种与疾病的发生有关
由于与人类组织取样相关的伦理问题,尚未确定特征的神经病原性感染。 具体目标 1 将研究来自血浆的无细胞病毒和来自淋巴组织和外周血单核的细胞相关病毒的迁移(基因流)。在感染过程中,通过纵向 PBMC/组织取样和对有或没有 CD8+ 淋巴细胞耗竭的猕猴进行脑活检,将细胞 (PBMC) 传输至 CNS。 具体目标 2 将测量 PBMC 的生物标志物。随着时间的推移,脑炎相关的脑损伤,以研究特定目标 1 中观察到的病毒进化和群体动态与疾病发作和进展之间的联系,最终,我们将能够确定脑感染的时空模式和导致的进化特征。
同样重要的是,这些发现可用于开发针对与神经发病机制相关的病毒和/或感染免疫细胞群的药物。迄今为止,该项目的主要研究人员 Marco Salemi 博士将对多种组织的纵向 SIV 序列进行最全面的分析,他在系统发育分析方面拥有丰富的经验,并致力于培养对 SIV 至关重要的资源丰富的环境。这个项目的成功以及我的预
此外,我们还组建了一个独特且合格的跨学科咨询委员会来协助监督和推进这项研究。
项目成果
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