Exploring the mechanism of ADAP1 control of HIV latency and reactivation in CD4 T cells

探索 ADAP1 控制 CD4 T 细胞中 HIV 潜伏期和再激活的机制

基本信息

  • 批准号:
    10082399
  • 负责人:
  • 金额:
    $ 24.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-01 至 2022-05-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Elimination of integrated, replication-competent HIV proviruses from host genomes persisting despite suppressive anti-retroviral therapy (ART) is the major roadblock to a functional cure. Cells harboring these types of proviruses produce marginal levels of viral products thereby becoming refractory to immune surveillance mechanisms. This lack of detection by the immune system, in addition to its increased growth potential, due to homeostatic proliferation and clonal expansion, extend the lifespan of latently infected cells generating a persistent reservoir. There is enormous enthusiasm for the potential of precision therapies targeting the latent reservoir in clinical settings. To achieve this major biomedical goal, we must first discover cell-intrinsic and/or -extrinsic “mediators” of reservoir persistence and latency-reactivation switch before we can leverage this knowledge for clinical intervention. To start filling this gap in knowledge, we implemented a gain- of-function screen in a CD4+ T cell line containing a latent provirus and discovered several novel regulators of the latency-reactivation switch. In this exploratory and developmental R21 grant proposal, we will focus our attention on one of those activators named ADAP1 (Arf-GAP with dual PH domain-containing protein-1). Importantly, ADAP1 has not been previously linked to immune cell biology nor to the control of HIV proviral gene regulation and latency, thus our studies hold conceptual innovation. Given these findings, the major objective of this research proposal is to achieve a better understanding of the molecular mechanisms underlying ADAP1 control of HIV latency and reactivation. To accomplish this, we will leverage the power of primary models of latency in a comprehensive set of CD4+ T cell effector subsets to understand complex and heterogeneous immune cell co-factor–HIV proviral genome interactions during latency and reactivation. The central hypothesis of this proposal is that ADAP1 is required to activate cell signaling-transcription regulatory programs in CD4+ T cell subsets while resting cells are exposed to immune cell stimulation/co-stimulation. Specifically, we will explore if ADAP1 functions to reactivate latent HIV from latency models in various CD4+ T cell subsets (Aim 1), and interrogate the ADAP1-regulated cell signaling- transcriptional programs leading to latent HIV reactivation (Aim 2). These studies could have a revolutionary impact on our understanding of HIV latency biology and have therapeutic implications. By elucidating how CD4+ T cell subsets shape the course of infection and how HIV co-opts host resources (like ADAP1) for the latency-reactivation switch, we will gain insights into basic processes as well as pathways that can be targeted therapeutically to help achieve NIAID mission’s of ending the HIV epidemic.
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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Ivan D'Orso其他文献

Ivan D'Orso的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Ivan D'Orso', 18)}}的其他基金

A chemical genetics approach for studies of HIV-1 latency
研究 HIV-1 潜伏期的化学遗传学方法
  • 批准号:
    10711683
  • 财政年份:
    2023
  • 资助金额:
    $ 24.51万
  • 项目类别:
Delineating ARF negative regulation of PAF1C-dependent oncogenic programs
描绘 ARF 对 PAF1C 依赖性致癌程序的负调控
  • 批准号:
    10437541
  • 财政年份:
    2022
  • 资助金额:
    $ 24.51万
  • 项目类别:
Delineating the Role of KAP1 in WNT-induced Colorectal Cancer
描述 KAP1 在 WNT 诱导的结直肠癌中的作用
  • 批准号:
    10358964
  • 财政年份:
    2022
  • 资助金额:
    $ 24.51万
  • 项目类别:
Delineating ARF negative regulation of PAF1C-dependent oncogenic programs
描绘 ARF 对 PAF1C 依赖性致癌程序的负调控
  • 批准号:
    10588156
  • 财政年份:
    2022
  • 资助金额:
    $ 24.51万
  • 项目类别:
Delineating the Role of KAP1 in WNT-induced Colorectal Cancer
描述 KAP1 在 WNT 诱导的结直肠癌中的作用
  • 批准号:
    10544512
  • 财政年份:
    2022
  • 资助金额:
    $ 24.51万
  • 项目类别:
Exploring the mechanism of ADAP1 control of HIV latency and reactivation in CD4 T cells
探索 ADAP1 控制 CD4 T 细胞中 HIV 潜伏期和再激活的机制
  • 批准号:
    10176412
  • 财政年份:
    2020
  • 资助金额:
    $ 24.51万
  • 项目类别:
Novel small molecules to reactivate latent HIV and sensitize to anti-viral therapies
新型小分子可重新激活潜伏的艾滋病毒并使抗病毒疗法敏感
  • 批准号:
    9535050
  • 财政年份:
    2016
  • 资助金额:
    $ 24.51万
  • 项目类别:
Novel small molecules to reactivate latent HIV and sensitize to anti-viral therapies
新型小分子可重新激活潜伏的艾滋病毒并使抗病毒疗法敏感
  • 批准号:
    9291553
  • 财政年份:
    2016
  • 资助金额:
    $ 24.51万
  • 项目类别:
Transcriptional regulatory mechanisms shaping HIV proviral fate
影响HIV原病毒命运的转录调控机制
  • 批准号:
    10322694
  • 财政年份:
    2015
  • 资助金额:
    $ 24.51万
  • 项目类别:
Transcriptional regulatory mechanisms shaping HIV proviral fate
影响HIV原病毒命运的转录调控机制
  • 批准号:
    9926935
  • 财政年份:
    2015
  • 资助金额:
    $ 24.51万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了