Exploring HIV-associated Neurocognitive Disorder (HAND) and HIV Latency at the Single Cell Level in Cerebral Organoids

在脑类器官的单细胞水平上探索 HIV 相关神经认知障碍 (HAND) 和 HIV 潜伏期

基本信息

  • 批准号:
    10466829
  • 负责人:
  • 金额:
    $ 70.8万
  • 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 2024-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary Fully half of all HIV-infected individuals continue to display some (often milder) form of HIV-associated neurocognitive disorder (HAND) despite the introduction of antiretroviral therapy (ART). More than one in 10 of these individuals will exhibit progressive neurologic deterioration on ART. More severe forms of HAND, including HIV-associated dementia, remain common in the developing world, especially in individuals not receiving ART. HAND is likely caused by chronic inflammation in the brain leading to neuronal dysfunction. The conundrum is how this inflammatory response is sustained despite effective suppression of viral replication with ART. We believe latent HIV infection of microglia likely plays a central role. Microglia comprise 10-15% of all cells in the CNS and serve as the brain's "constant gardeners" shaping neuronal plasticity through synaptic pruning and stripping; microglia also participate in bidirectional signaling with closely intertwined neurons. How best to study these microglia, their interplay with neurons, and the effects of HIV infection? We propose to coculture two iPSC- derived sub-lines engineered to express doxycycline-inducible transcription factors that are sufficient to drive differentiation into either microglia or excitatory neurons. When induced and cocultured in 3D conditions, these cells form cerebral microorganoids (CMs) that recapitulate many of the cytoarchitectural features and functions of the fetal brain. We will study these CMs in an unbiased manner using scRNA-seq to define gene expression profiles and scATAC-sec to interrogate chromatin accessibility. Use of a combinatorial indexing system of barcodes will allow measurement of these parameters in the same cell. We hypothesize that microglia are latently infected and that sustained neuronal neurotransmitter signaling is likely sufficient to reactivate virus expression plus exposure to opioids will further enhance reactivation (virus production is not impaired by ART). Release of reactivated virions may directly trigger a chronic inflammatory response. Additionally, when these viruses are transmitted cell-to-cell, an abortive form of HIV infection may ensue due to the action of the RT inhibitors present in ART. The IFI16 DNA sensor may detect these RT products leading to inflammasome assembly, caspase-1 activation, production of IL-1β and IL-18 and death by pyroptosis, a highly inflammatory form of programmed cell death. Because pyroptosis breeds more pyroptosis, this feed-forward form of inflammation could a create chronic inflammatory response resistant to ART. Finally, we are eager to explore two CNS-tailored approaches for attacking the latent HIV reservoir in microglia. In the first, virus will be purged with a CNS-penetrant LRA and cells producing viral RNA will be selectively killed by induction of RIG-I-dependent apoptosis. In the second, durable, sequence-specific transcriptional silencing of HIV proviruses will be tested using CRISPR interference to promote H3K9me3 and DNA methylation––both epigenetic modifications are needed for long term silencing. Together, these studies promise to provide new and exciting insights into HAND pathogenesis, HIV latency in the brain, effects of opioids, and the potential link between these processes.
项目总结

项目成果

期刊论文数量(0)
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Melanie Maria Ott其他文献

Melanie Maria Ott的其他文献

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{{ truncateString('Melanie Maria Ott', 18)}}的其他基金

In vitro virology core
体外病毒学核心
  • 批准号:
    10512624
  • 财政年份:
    2022
  • 资助金额:
    $ 70.8万
  • 项目类别:
Modeling intestinal dysfunction in HIV infection with organoid technology
利用类器官技术模拟 HIV 感染的肠道功能障碍
  • 批准号:
    10542390
  • 财政年份:
    2020
  • 资助金额:
    $ 70.8万
  • 项目类别:
Modeling intestinal dysfunction in HIV infection with organoid technology
利用类器官技术模拟 HIV 感染的肠道功能障碍
  • 批准号:
    9894660
  • 财政年份:
    2020
  • 资助金额:
    $ 70.8万
  • 项目类别:
Modeling intestinal dysfunction in HIV infection with organoid technology
利用类器官技术模拟 HIV 感染的肠道功能障碍
  • 批准号:
    10083740
  • 财政年份:
    2020
  • 资助金额:
    $ 70.8万
  • 项目类别:
Modeling intestinal dysfunction in HIV infection with organoid technology
利用类器官技术模拟 HIV 感染的肠道功能障碍
  • 批准号:
    10322720
  • 财政年份:
    2020
  • 资助金额:
    $ 70.8万
  • 项目类别:
Single-Cell Transcriptomics of Non-Activated Latently Infected T cells Isolated from HIV+ Drug Users
从 HIV 吸毒者中分离出的非激活潜伏感染 T 细胞的单细胞转录组学
  • 批准号:
    10548752
  • 财政年份:
    2019
  • 资助金额:
    $ 70.8万
  • 项目类别:
Harnessing the RNA-Binding Properties of Cas13a for HIV-1 Self-Testing
利用 Cas13a 的 RNA 结合特性进行 HIV-1 自检
  • 批准号:
    10423661
  • 财政年份:
    2019
  • 资助金额:
    $ 70.8万
  • 项目类别:
Harnessing the RNA-Binding Properties of Cas13a for HIV-1 Self-Testing
利用 Cas13a 的 RNA 结合特性进行 HIV-1 自检
  • 批准号:
    10456229
  • 财政年份:
    2019
  • 资助金额:
    $ 70.8万
  • 项目类别:
Exploring HIV-associated Neurocognitive Disorder (HAND) and HIV Latency at the Single Cell Level in Cerebral Organoids
在脑类器官的单细胞水平上探索 HIV 相关神经认知障碍 (HAND) 和 HIV 潜伏期
  • 批准号:
    10678898
  • 财政年份:
    2019
  • 资助金额:
    $ 70.8万
  • 项目类别:
PROJECT 2: Determine clinically relevant host-viral dependency networks for respiratory infections including SARS-CoV-2
项目 2:确定呼吸道感染(包括 SARS-CoV-2)的临床相关宿主病毒依赖性网络
  • 批准号:
    10550002
  • 财政年份:
    2018
  • 资助金额:
    $ 70.8万
  • 项目类别:

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