Mechanisms and Therapeutic Targeting of CD4 Down regulation in African Green Monkeys

非洲绿猴 CD4 下调的机制和治疗目标

基本信息

  • 批准号:
    10254703
  • 负责人:
  • 金额:
    $ 28.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2023-01-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Given the success of fully-suppressive antiretroviral therapy (ART) regimens, efforts have shifted over the past decade to strategies aimed at eradicating the body of HIV. The vast majority of these strategies tested in vivo have relied on some form of the “shock and kill” approach. To date, all of these studies have failed to accelerate decay of the HIV reservoir. These outcomes highlight both the long road to refinement of current shock and kill approaches and the need to explore alternative HIV cure avenues. An approach with significant promise in this setting relies on experimentally ablating CCR5 to render cells resistant to HIV-1 infection. Natural hosts of SIV circumvent disease progression in spite of ongoing viremia and have evolved to naturally regulate HIV-1/SIV entry receptors. African green monkeys (AGMs), in particular, post- thymically down-regulate CD4 to become refractory to SIV infection, a process resulting in anecdotal instances of AGMs evidently curing themselves of SIV. Despite the profound consequences, the molecular events governing this process are entirely undefined. Our previous studies revealed that CD4 down-regulation is mediated in part by DNA hypermethylation of the CD4 promoter region. In this study we will examine the overall hypothesis that CD4 locus methylation in AGMs is the result of uniquely regulated trans-acting factors and manipulating these trans-acting in progressive host CD4 T cells can induce CD4 instability and phenocopy the virus-resistant qualities of AGM T cells. We identified two particular trans-acting factors uniquely regulated in AGM T cells that lose CD4. In aim 1 we will focus on the Ten-eleven translocation protein 3 (TET3), a DNA demethylase found to be down-regulated upon loss of CD4 in AGMs. In aim 2 we will focus on the wnt signaling transcription factor TCF-1, which we find to be uniquely down-regulated upon AGM CD4 down-regulation. Both aims will follow a similar workflow to causatively determine the role of these factors in CD4 regulation. By lentiviral transduction, we will determine if over-expression of TET3 or TCF-1 rescues CD4 on the surface of AGM T cells. We will then employ CRISPR-cas9 gene editing techniques, asking if genetic ablation of these factors in rhesus or human cells can promote CD4 instability, and whether this leads to virus resistance by in vitro infection assays. These aims test an overall model of CD4 gene promoter regulation based on natural host co-evolution with SIV. The proposed experiments will extend this model to progressive hosts in the hopes of implementing a “bulletproof” strategy to render T cells resistant to all HIV-1/SIV strains, regardless of tropism. If successful, the proposed studies will generate data for a more comprehensive proposal aimed at in vivo studies of autologously- transferred, virus-resistant T cells.
项目总结/文摘

项目成果

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Joseph Christopher Mudd其他文献

Joseph Christopher Mudd的其他文献

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{{ truncateString('Joseph Christopher Mudd', 18)}}的其他基金

Early intervention with anti-proliferative therapy close to ART initiation to limit long-term SIV persistence
在 ART 开始时进行早期抗增殖治疗干预,以限制 SIV 的长期持续存在
  • 批准号:
    10849960
  • 财政年份:
    2023
  • 资助金额:
    $ 28.95万
  • 项目类别:
The intersection of diet, cell metabolic state, and SIV reservoir transcription
饮食、细胞代谢状态和 SIV 储存库转录的交叉点
  • 批准号:
    10618546
  • 财政年份:
    2023
  • 资助金额:
    $ 28.95万
  • 项目类别:
Role of RhCMV in shaping the SIV proviral landscape
RhCMV 在塑造 SIV 前病毒景观中的作用
  • 批准号:
    10541869
  • 财政年份:
    2022
  • 资助金额:
    $ 28.95万
  • 项目类别:
Role of RhCMV in shaping the SIV proviral landscape
RhCMV 在塑造 SIV 前病毒景观中的作用
  • 批准号:
    10397879
  • 财政年份:
    2022
  • 资助金额:
    $ 28.95万
  • 项目类别:
Mechanisms and Therapeutic Targeting of CD4 Down regulation in African Green Monkeys
非洲绿猴 CD4 下调的机制和治疗目标
  • 批准号:
    10378164
  • 财政年份:
    2021
  • 资助金额:
    $ 28.95万
  • 项目类别:
Innate Lymphoid Cell Loss in HIV-1 and SIV Infection
HIV-1 和 SIV 感染中的先天淋巴细胞损失
  • 批准号:
    9618331
  • 财政年份:
    2020
  • 资助金额:
    $ 28.95万
  • 项目类别:

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