CBF-1 role in regulating HIV reservoir in microglial cells

CBF-1在调节小胶质细胞中HIV储存库中的作用

基本信息

  • 批准号:
    10626867
  • 负责人:
  • 金额:
    $ 23.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-06-01 至 2024-05-31
  • 项目状态:
    已结题

项目摘要

Project Summary: Although the resting memory CD4+ T cells are the best-recognized long-lived reservoirs of latent HIV provirus, it is now well accepted that the myeloid cells, especially of the central nervous system (CNS)- -including perivascular macrophages and microglial cells--can also contribute to viral reservoirs. The molecular mechanisms relevant to HIV latency are primarily defined by analyzing HIV latency in latently infected CD4+ lymphoid cells. However, very little is known about HIV latency/persistence in myeloid cells. Notably, the presence of HIV-harboring myeloid cells in the CNS are documented to be the key factor contributing to CNS inflammation and promoting HIV-associated neurocognitive disorder (HAND) in HIV patients. Microglial cells are the main HIV reservoir in the CNS, yet a gap in the knowledge regarding our understanding of the molecular mechanisms that maintains HIV reservoirs in those cells. Our long term goal is identifying and characterizing the underlying molecular mechanisms that regulate HIV latency in microglial cells. The important role of CBF-1-mediated transcriptional inhibition during HIV latency is well established in lymphoid cells. The objective of this grant is to characterize the role of CBF-1 during HIV latency in microglial cells. Based on our published and preliminary findings, we have hypothesized that, similar to lymphocytes, in microglial cells CBF- 1 promotes HIV latency/slowdown by inducing the generation of transcriptionally-repressive heterochromatin structures at HIV LTR. Our rationale is that since HIV latency is primarily regulated at the transcriptional level, defining the precise mechanism(s) that regulate HIV transcription in microglial cells will offer new therapeutic opportunities to target HIV reservoirs in the CNS. In Aim 1, we will examine the role of CBF-1-induced epigenetic changes in restricting HIV transcription and their eventual impact on the establishment and the maintenance phases of HIV latency. In Aim 2, we will characterize the corepressor complexes that CBF-1 recruits at HIV LTR and their functional significance in promoting HIV reservoir in microglial cells. Upon conclusion, we will be able to define the CBF-1-mediated mechanisms that facilitate the establishment and maintenance of HIV latency in microglial cells. These studies will also provide a well-defined therapeutic target in the form of CBF-1 and its corepressor complexes in order to relieve multiple repressive epigenetic modifications simultaneously. Proposed research is innovative because it uses human primary microglial cells, and a novel ex vivo model system for HIV latency in microglial cells that, for the first time, allows the studies of the molecular correlates for HIV entry and exit into latency in microglial cells, which is otherwise an impossible task due to insufficient availability of brain autopsy specimens. This contribution is significant since the identified mechanisms, which regulate HIV transcription and latency in microglial cells, will facilitate the designing of optimized therapies targeting CNS reservoirs of HIV, contributing to cure approaches.
项目总结:虽然静息记忆CD4+ T细胞是公认的最长寿的

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Mudit Tyagi其他文献

Mudit Tyagi的其他文献

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{{ truncateString('Mudit Tyagi', 18)}}的其他基金

CBF-1 role in regulating HIV reservoir in microglial cells
CBF-1在调节小胶质细胞中HIV储存库中的作用
  • 批准号:
    10403065
  • 财政年份:
    2022
  • 资助金额:
    $ 23.4万
  • 项目类别:
Characterization of cocaine induced signaling pathways that enhances HIV transcription
可卡因诱导的增强 HIV 转录的信号通路的表征
  • 批准号:
    9554849
  • 财政年份:
    2017
  • 资助金额:
    $ 23.4万
  • 项目类别:
Characterization of cocaine induced signaling pathways that enhances HIV transcription
可卡因诱导的增强 HIV 转录的信号通路的表征
  • 批准号:
    10399877
  • 财政年份:
    2017
  • 资助金额:
    $ 23.4万
  • 项目类别:
Characterization of cocaine induced signaling pathways that enhances HIV transcription
可卡因诱导的增强 HIV 转录的信号通路的表征
  • 批准号:
    9926231
  • 财政年份:
    2017
  • 资助金额:
    $ 23.4万
  • 项目类别:
Characterization of cocaine induced signaling pathways that enhances HIV transcription
可卡因诱导的增强 HIV 转录的信号通路的表征
  • 批准号:
    10611835
  • 财政年份:
    2017
  • 资助金额:
    $ 23.4万
  • 项目类别:
Cocaine induced selective epigenetic and signaling pathways enhance HIV replicati
可卡因诱导选择性表观遗传和信号通路增强 HIV 复制
  • 批准号:
    8610274
  • 财政年份:
    2013
  • 资助金额:
    $ 23.4万
  • 项目类别:
Cocaine induced selective epigenetic and signaling pathways enhance HIV replicati
可卡因诱导选择性表观遗传和信号通路增强 HIV 复制
  • 批准号:
    8330018
  • 财政年份:
    2013
  • 资助金额:
    $ 23.4万
  • 项目类别:
Cocaine enhances HIV replication by inducing transcriptionally active chromatin s
可卡因通过诱导转录活性染色质增强 HIV 复制
  • 批准号:
    8329932
  • 财政年份:
    2012
  • 资助金额:
    $ 23.4万
  • 项目类别:
Cocaine enhances HIV replication by inducing transcriptionally active chromatin s
可卡因通过诱导转录活性染色质增强 HIV 复制
  • 批准号:
    8586519
  • 财政年份:
    2012
  • 资助金额:
    $ 23.4万
  • 项目类别:

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早期抗 HIV 治疗的儿科免疫相关性
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