Regulation of HIV latency by microglial-neuronal interactions

小胶质细胞-神经元相互作用对 HIV 潜伏期的调节

基本信息

  • 批准号:
    10674037
  • 负责人:
  • 金额:
    $ 78.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-15 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Summary Over 40% of HIV-positive individuals in the United States engage in substance use. This not only represents a major cause of enhanced morbidity and mortality, but also is associated with increased risks of neurocognitive disorders, such as HAND. Neurons possess refined systems for maintaining constant communication with glia through propagation of “Off” and “On” signals controlling microglial activation states. Using HIV latency models in immortalized human microglial cells (hµglia/HIV), we have shown previously that cellular activation and inflammatory responses induce HIV production. Remarkably, co-culture of productively infected microglia with an excess of healthy neurons leads to viral silencing. We have also shown that hµglia/HIV cells can migrate into brain organoids where they become silenced. However, damaging neurons with a variety of agents, including methamphetamine (METH), a frequently-used abuse substance among HIV-infected individuals, produce reactivation signals for HIV, and this initiates a cycle of microglial activation and further neuronal damage. This cycle of shutdown and reactivation seems to parallel the M1 to M2 transition model of microglial cells, much as HIV latency in T cells is a product of the natural transition of effector cells to resting memory cells. In this proposal, we seek to define the key signals mediating the cycle of viral silencing and reactivation in microglial cells by neurons in the context of iPSC-derived cerebral organoids. This multidisciplinary investigation is designed as a close collaboration between the laboratories of Dr. Jonathan Karn (CWRU, HIV molecular biology), Dr. Anthony Wynshaw-Boris (CWRU, iPSC cells, brain organoids), Dr. Kurt Hauser (VCU, neurobiology and drug abuse), and Dr. Pamela Knapp (VCU, brain organoids). To avoid the limitations of working with transformed cells, we have recently initiated experiments using co-cultures between iPSC-derived cerebral organoids and microglia. Using co-cultures between iPSC-derived cerebral organoids and microglia, we will thoroughly test the hypothesis that the exaggerated responses of HIV-infected microglia to neuronal damage leads to enhanced neurodegeneration. We will also test the hypothesis that exposure to METH, given this background of faulty microglia-neuron crosstalk, enhances HIV replication. Using genome editing approaches, we will identify the specific contribution of “On” and “Off” receptor systems in controlling HIV latency in microglia, and study how METH impacts neuronal-microglial signaling to augment HIV production. In parallel with our genetic investigations, we will also evaluate a number of pharmacological agents against microglial receptors, HIV transcription inhibitors, and mediators of inflammation in order to define therapeutic approaches that might be expected to slow the development of HAND, especially in patients who abuse drugs.
总结

项目成果

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JONATHAN KARN其他文献

JONATHAN KARN的其他文献

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{{ truncateString('JONATHAN KARN', 18)}}的其他基金

The role of RNA m6A modification in the regulation of HIV latency and reactivation
RNA m6A 修饰在调节 HIV 潜伏和再激活中的作用
  • 批准号:
    10600078
  • 财政年份:
    2022
  • 资助金额:
    $ 78.49万
  • 项目类别:
The role of RNA m6A modification in the regulation of HIV latency and reactivation
RNA m6A 修饰在调节 HIV 潜伏和再激活中的作用
  • 批准号:
    10461499
  • 财政年份:
    2022
  • 资助金额:
    $ 78.49万
  • 项目类别:
Research Support Core B: Primary Cell, Biomimetic, and iPSC-derived Cell Models
研究支持核心 B:原代细胞、仿生和 iPSC 衍生细胞模型
  • 批准号:
    10304584
  • 财政年份:
    2021
  • 资助金额:
    $ 78.49万
  • 项目类别:
Research Support Core B: Primary Cell, Biomimetic, and iPSC-derived Cell Models
研究支持核心 B:原代细胞、仿生和 iPSC 衍生细胞模型
  • 批准号:
    10632094
  • 财政年份:
    2021
  • 资助金额:
    $ 78.49万
  • 项目类别:
New Inhibitors of HIV latency reactivation
HIV潜伏期再激活的新抑制剂
  • 批准号:
    10010720
  • 财政年份:
    2020
  • 资助金额:
    $ 78.49万
  • 项目类别:
New Inhibitors of HIV latency reactivation
HIV潜伏期再激活的新抑制剂
  • 批准号:
    10208701
  • 财政年份:
    2020
  • 资助金额:
    $ 78.49万
  • 项目类别:
Control of P-TEFb biogenesis and HIV transcription in primary T-cells
原代 T 细胞中 P-TEFb 生物发生和 HIV 转录的控制
  • 批准号:
    10158438
  • 财政年份:
    2019
  • 资助金额:
    $ 78.49万
  • 项目类别:
Regulation of HIV latency by microglial-neuronal interactions
小胶质细胞-神经元相互作用对 HIV 潜伏期的调节
  • 批准号:
    10220927
  • 财政年份:
    2019
  • 资助金额:
    $ 78.49万
  • 项目类别:
Control of P-TEFb biogenesis and HIV transcription in primary T-cells
原代 T 细胞中 P-TEFb 生物发生和 HIV 转录的控制
  • 批准号:
    10403547
  • 财政年份:
    2019
  • 资助金额:
    $ 78.49万
  • 项目类别:
Control of P-TEFb biogenesis and HIV transcription in primary T-cells
原代 T 细胞中 P-TEFb 生物发生和 HIV 转录的控制
  • 批准号:
    10629307
  • 财政年份:
    2019
  • 资助金额:
    $ 78.49万
  • 项目类别:

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