Effect of drugs of abuse on CNS HIV-1 reservoirs and neuropathogenesis
滥用药物对 CNS HIV-1 储存库和神经发病机制的影响
基本信息
- 批准号:9977143
- 负责人:
- 金额:$ 62.57万
- 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:2016-09-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAnatomyAnti-Retroviral AgentsAstrocytesAutomationAutopsyBiological AssayBiological ModelsBlood - brain barrier anatomyBrainCD4 Positive T LymphocytesCannabisCell Culture TechniquesCell LineCell modelCellsCocaineConsumptionDevelopmentDrug ScreeningDrug abuseFrequenciesFutureGenetic TranscriptionGoalsHIVHIV-1HumanIllicit DrugsImmunofluorescence ImmunologicIn VitroIndividualInfectionKineticsKnowledgeMeasuresMethamphetamineMethodsMicrogliaModelingNational NeuroAids Tissue ConsortiumNatureNeuraxisNeuropathogenesisPatientsPopulationProteinsProvirusesRNAReactionRecording of previous eventsResolutionRestRoleSamplingScanningShockSlideSolidSpeedTestingTimeTissuesViralViral Load resultVirusbasecell typedrug of abuseillicit drug usemacrophagememory CD4 T lymphocytemethamphetamine effectmonocytenovelpatient populationperipheral bloodpreventreactivation from latencyresponsesingle moleculespecific biomarkerstool
项目摘要
Project summary
The long term goal of this application is to study HIV-1 reservoirs that persist in CNS and to understand
the role of illicit drugs in establishing and reactivating the latent reservoirs. Persistence of latently infected cells
in CNS poses a major barrier for HIV-1 eradication. Current strategies to eliminate the latent reservoirs include
a “shock and kill” therapy and is aimed at peripheral blood, which constitutes only 1% of the total reservoirs.
Whether it is possible to envision similar strategies for the eradication of HIV-infected CNS cells is currently
unknown. In addition to the lack of knowledge about latency in CNS HIV+ cells and the effects of latency
reversing agents, illicit drugs common within the HIV-infected populations constitute a further complexity. Many
illicit drugs are known to stimulate HIV-1 replication. Since the current method to measure the peripheral blood
HIV reservoir is not applicable to solid tissues or to cells that replicate poorly such as macrophages, microglia
and astrocytes found in the brain. We have developed a novel, Single cell-single molecule, Multiplex,
Immunofluorescence (IF) and RNA FISH-based Assay (SMIRA) to detect cells in which HIV-1 is actively
replicating. Using automation, a large number of cells can be scanned. In this proposal, we will employ this
novel method to first quantitate and characterize latency in cell line models, then the latent reservoirs in brain
derived microglia and astrocytes and delineate the effect of three drugs of abuse (methamphetamine, cocaine
and cannabis) on the efficiency of formation of latent cells, the rate of reactivation of latent cells, and
establishment of latency across blood-brain-barrier (BBB). Three Aims are proposed. In Aim 1, we will study
the role of illicit drugs on the reactivation of latently infected CNS-derived cells by establishing in vitro and ex
vivo models of latency. First, we will employ immortalized human monocyte and microglial cell lines to study
the kinetics of reactivation and the effect of METH, Cocaine and cannabis on the reactivation using SMIRA.
This will be followed by similar studies using a primary CNS cells. In Aim 2, we will study the role of illicit drugs
on the establishment of HIV reservoirs in CNS cells across BBB. Using SMIRA to detect HIV-1+ cells, we will
determine the relative effect of drugs of abuse, antiretrovirals and the addition of LRAs to establish latency
across BBB. In Aim 3, we will study the effect of illicit drugs on CNS HIV reservoirs in HIV-infected individuals.
Employing brain autopsy samples from HIV+ individuals with or without illicit drug use history (from the
Manhattan Brain Bank (NNTC), we will characterize the relative frequency of microglial and astrocyte latent cell
reservoirs in which HIV-1 is actively replicating vs. those that are latent, using SMIRA and state-of-the-art,
high-speed/resolution whole slide scanner, the PerkinElmer Pannoramic 250 Flash II. We will study the effect
of drug abuse on the rates of reactivation. The proposed studies will provide valuable tools to study
establishment and reactivation of CNS latency in response to illicit drugs and provides a drug screening assay
to eradicate these latent cells in the future.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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GANJAM V KALPANA其他文献
GANJAM V KALPANA的其他文献
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Effect of drugs of abuse on CNS HIV-1 reservoirs and neuropathogenesis
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$ 62.57万 - 项目类别:
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- 资助金额:
$ 62.57万 - 项目类别:
Effect of drugs of abuse on CNS HIV-1 reservoirs and neuropathogenesis
滥用药物对 CNS HIV-1 储存库和神经发病机制的影响
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