Evaluation of didehydro-Cortistatin A as a block-and-lock agent for a functional HIV cure in a macaque model

双脱氢皮质抑素 A 作为阻断剂在猕猴模型中功能性 HIV 治愈的评价

基本信息

  • 批准号:
    10591883
  • 负责人:
  • 金额:
    $ 45.09万
  • 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:
    2021-09-20 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

Abstract A reservoir of latently infected cells persists in various anatomical sites in people living with HIV (PLWH), despite effective virological control by antiretroviral therapy (ART). The majority of virally suppressed individuals experience rapid viral rebound upon ART interruption, providing a strong rationale for the development of cure strategies. Even in an ART-suppressed HIV infection, chronic inflammation and immune activation are observed, along with limited CD4+T cell reconstitution, mucosal immune dysfunction, co-morbidities, and accelerated ageing. Low-grade persistent transcription and trickling production of viral proteins from the pool of integrated proviruses are believed to be partly responsible for these conditions. HIV eradication strategies such as shock- and-kill have not been successful so far, and the pursuit of a functional cure or HIV remission has been thought as an alternative worth exploring. A functional cure entails long-term, durable control of viral expression in the absence of therapy, preventing disease progression and transmission, despite the presence of detectable integrated proviruses. Our group has been at the forefront of developing one such strategy, labeled the block- and-lock approach. The premise of this approach is that transcriptional inhibitors can mediate epigenetic silencing of proviral expression, locking the virus in a profound state of latency from which reactivation is very unlikely to occur upon ART discontinuation. We have demonstrated this principle using the small molecule didehydro-Cortistatin A (dCA) inhibitor of Tat, the key regulator of HIV transcriptional amplification. In in vitro and in humanized mouse models of HIV latency, dCA inhibition of HIV transcription over time drives the viral promoter into deep transcriptional inhibition, limiting viral reactivation upon treatment interruption or with latency reactivating agents (LRAs)1–8. We believe that HIV transcriptional inhibitors, in general, have the potential to transform the way we treat HIV- 1 infections. Here we propose to investigate the potential of adding the transcriptional inhibitor dCA to an ART regimen in the rhesus macaque (RhM) model of SHIV infection. Not only is dCA a new molecule that inhibits the activity of a viral target not yet clinically explored, but it also opens the possibility for exploration of novel approaches to fight HIV. Here we propose to: 1) determine the safety and pharmacokinetics of dCA in ART- treated RhMs; 2) understand the relationship between dCA treatment and reduction in viral RNA in tissues, with the time to viral rebound upon treatment interruption; and 3) study the impact of dCA as front-line therapy on the size of the established viral reservoir.
摘要

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 }}

David T Evans其他文献

David T Evans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('David T Evans', 18)}}的其他基金

Evaluation of didehydro-Cortistatin A as a block-and-lock agent for a functional HIV cure in a macaque model
双脱氢皮质抑素 A 作为阻断剂在猕猴模型中功能性 HIV 治愈的评价
  • 批准号:
    10403162
  • 财政年份:
    2021
  • 资助金额:
    $ 45.09万
  • 项目类别:
Tethering lentiviral restriction to Fc-mediated antibody responses
将慢病毒限制与 Fc 介导的抗体反应结合起来
  • 批准号:
    10425358
  • 财政年份:
    2020
  • 资助金额:
    $ 45.09万
  • 项目类别:
Tethering lentiviral restriction to Fc-mediated antibody responses
将慢病毒限制与 Fc 介导的抗体反应结合起来
  • 批准号:
    10082732
  • 财政年份:
    2020
  • 资助金额:
    $ 45.09万
  • 项目类别:
Tethering lentiviral restriction to Fc-mediated antibody responses
将慢病毒限制与 Fc 介导的抗体反应结合起来
  • 批准号:
    10203816
  • 财政年份:
    2020
  • 资助金额:
    $ 45.09万
  • 项目类别:
Tethering lentiviral restriction to Fc-mediated antibody responses
将慢病毒限制与 Fc 介导的抗体反应结合起来
  • 批准号:
    10661036
  • 财政年份:
    2020
  • 资助金额:
    $ 45.09万
  • 项目类别:
Assessing ADCC and Fc-mediated Protection against HIV
评估 ADCC 和 Fc 介导的 HIV 保护作用
  • 批准号:
    10671615
  • 财政年份:
    2019
  • 资助金额:
    $ 45.09万
  • 项目类别:
Assessing ADCC and Fc-mediated Protection against HIV
评估 ADCC 和 Fc 介导的 HIV 保护作用
  • 批准号:
    10808458
  • 财政年份:
    2019
  • 资助金额:
    $ 45.09万
  • 项目类别:
Assessing ADCC and Fc-mediated Protection against HIV
评估 ADCC 和 Fc 介导的 HIV 保护作用
  • 批准号:
    10226317
  • 财政年份:
    2019
  • 资助金额:
    $ 45.09万
  • 项目类别:
Assessing ADCC and Fc-mediated Protection against HIV
评估 ADCC 和 Fc 介导的 HIV 保护作用
  • 批准号:
    10458659
  • 财政年份:
    2019
  • 资助金额:
    $ 45.09万
  • 项目类别:
Fcgamma receptor-mediated suppression of immunodeficiency virus replication
Fcγ受体介导的免疫缺陷病毒复制抑制
  • 批准号:
    9275920
  • 财政年份:
    2015
  • 资助金额:
    $ 45.09万
  • 项目类别:

相似海外基金

The role of 3'-Deoxy-3',4'-didehydro-cytidine in the host response to viral infections.
3-脱氧-3,4-二脱氢胞苷在宿主对病毒感染的反应中的作用。
  • 批准号:
    MR/W023865/1
  • 财政年份:
    2022
  • 资助金额:
    $ 45.09万
  • 项目类别:
    Fellowship
Evaluation of didehydro-Cortistatin A as a block-and-lock agent for a functional HIV cure in a macaque model
双脱氢皮质抑素 A 作为阻断剂在猕猴模型中功能性 HIV 治愈的评价
  • 批准号:
    10403162
  • 财政年份:
    2021
  • 资助金额:
    $ 45.09万
  • 项目类别:
ACTG240--ZIDOVUDINE VS 2,3-DIDEHYDRO-3'DEOXYTHYMIDINE IN HIV+ CHILDREN
ACTG240--齐多夫定与 2,3-二氢-3脱氧胸苷治疗 HIV 儿童
  • 批准号:
    6247868
  • 财政年份:
    1997
  • 资助金额:
    $ 45.09万
  • 项目类别:
BMY-27857 (2'3'-DIDEHYDRO-3'-DEOXYTHYMIDINE, D4T) ADMINISTERED TO HIV+ PATIENTS
BMY-27857(23-二氢-3-脱氧胸苷,D4T)用于 HIV 患者
  • 批准号:
    3849039
  • 财政年份:
  • 资助金额:
    $ 45.09万
  • 项目类别:
ZIDOVUDINE VS 2',3'DIDEHYDRO-3'DEOXYTHYMIDINE IN CHILDREN
齐多夫定与 2,3二氢-3脱氧胸苷在儿童中的比较
  • 批准号:
    3742272
  • 财政年份:
  • 资助金额:
    $ 45.09万
  • 项目类别:
ACTG 240--TRIAL OF ZDV VS 2',3' DIDEHYDRO 3' D4T IN CHILDREN WITH HIV INFECTION
ACTG 240--ZDV 与 2,3 二氢 3 D4T 在 HIV 感染儿童中的试验
  • 批准号:
    5224952
  • 财政年份:
  • 资助金额:
    $ 45.09万
  • 项目类别:
BMY-27857 (2'3'-DIDEHYDRO-3'-DEOXYTHYMIDINE, D4T) ADMINISTERED TO HIV+ PATIENTS
BMY-27857(23-二氢-3-脱氧胸苷,D4T)用于 HIV 患者
  • 批准号:
    3785276
  • 财政年份:
  • 资助金额:
    $ 45.09万
  • 项目类别:
ZIDOVUDINE VS 2,3-DIDEHYDRO-3 DEOXYTHYMIDINE IN HIV+ CHILDREN
齐多夫定 VS 2,3-二氢-3 脱氧胸苷治疗 HIV 儿童
  • 批准号:
    3742165
  • 财政年份:
  • 资助金额:
    $ 45.09万
  • 项目类别:
ZIDOVUDINE VS 2,3-DIDEHYDRO-3 DEOXYTHYMIDINE IN HIV+ CHILDREN
齐多夫定 VS 2,3-二氢-3 脱氧胸苷治疗 HIV 儿童
  • 批准号:
    5220083
  • 财政年份:
  • 资助金额:
    $ 45.09万
  • 项目类别:
BMY-27857 (2'3'-DIDEHYDRO-3'-DEOXYTHYMIDINE, D4T) ADMINISTERED TO HIV+ PATIENTS
BMY-27857(23-二氢-3-脱氧胸苷,D4T)用于 HIV 患者
  • 批准号:
    3763201
  • 财政年份:
  • 资助金额:
    $ 45.09万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了