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

基本信息

  • 批准号:
    10618546
  • 负责人:
  • 金额:
    $ 25.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-10 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract The main obstacle to curing HIV-1 infection is a reservoir that consists of resting memory CD4 T cells whose genomes contain inducible and replication-competent HIV-1 proviruses. Decay of the reservoir is slow and this has reinforced a notion that proviral HIV-1 DNA is largely transcriptionally silent. A wide body of recent evidence has pointed to the contrary. At any point in time, a non-negligible fraction of the HIV-1 reservoir remains transcriptionally active despite complete suppression with antiretroviral therapy (ART). Moreover, latent HIV-1 transcription can be induced above these apparent baseline levels with HIV-1 stimulatory compounds, deemed latency reversal agents (LRAs). Some LRAs have been able to modestly reduce reservoir size in small clinical or pre-clinical trials of HIV-1+ humans or SIV+ rhesus macaques (RMs). However, a current limitation of LRA use is that to date, these agents have been tested only in very narrow patient/animal cohorts, not representative of heterogeneity that exists in the HIV-1+ population, and not accounting for age, gender, or the prevalence of additional co-morbidities associated with HIV-1. Type 2 diabetes in particular is a co- morbidity that is prevalent in PLWH, and is the result of an imbalance of the dietary hormone insulin. In preliminary studies, we find that CD4 T cells (which serve as the principle reservoir for HIV-1) express the insulin receptor and respond to insulin by activating the PI3K signaling pathway. PI3K signaling is known to be upstream of (1) metabolic regulators of latent HIV-1 transcription (mTORC signaling) and (2) transcription factors involved in binding to the HIV-1 promoter (Sp1 and FOXO1). In these proposed studies, we will take advantage of an existing well-powered cohort of fully ART-suppressed SIV+ RMs to probe the role of insulin signaling as a regulator of the HIV-1/SIV lifecycle. We will employ cutting-edge phospho-proteomic methods to examine how the dietary hormone insulin influences transcription of latent SIV in (Aim 1) the context of LRA-based biologics that share common signaling cascades with insulin and (Aim 2) the context of natural blood glucose/insulin fluctuations that occur with dietary intake. The application will seek to define on a basic level (1) the insulin “signalome” in CD4 T cells (2) as-yet explored dietary factors that may influence transcriptional activity of latent HIV-1 and importantly (3) provide a conceptual framework for future studies on LRA use in settings in which insulin signaling is impaired.
项目总结/文摘

项目成果

期刊论文数量(0)
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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:
    $ 25.43万
  • 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:
    $ 25.43万
  • 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:
    $ 25.43万
  • 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:
    $ 25.43万
  • 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:
    10254703
  • 财政年份:
    2021
  • 资助金额:
    $ 25.43万
  • 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:
    $ 25.43万
  • 项目类别:

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