Identification and characterization of chromatin regulators of HIV-1 latency

HIV-1 潜伏期染色质调节因子的鉴定和表征

基本信息

  • 批准号:
    10423663
  • 负责人:
  • 金额:
    $ 48.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-01 至 2022-04-01
  • 项目状态:
    已结题

项目摘要

Abstract After HIV integration of the proviral DNA into the host genome, the virus can remain latent or activate transcription. The viral Tat protein, which enhances transcript elongation from the HIV-1 promoter, is the switch between these two states. Since Tat resides under the control of the same promoter, it enhances its own transcription via a positive feedback loop. We identified didehydro-Cortistatin A (dCA) as a very potent inhibitor of Tat (1, 2). In human CD4 +T cells isolated from aviremic individuals, combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound during treatment interruption, as the HIV-1 promoter remains epigenetically repressed. HIV-1 transcriptional inhibitors have the unique property of reducing particle production from infected cells. dCA is the proof-of-concept that this novel class of molecules is amenable to block-and-lock functional cure approaches, which aim at reducing residual viremia during ART and limit viral rebound. It is thus important to understand the mechanisms that explain not only dCA's inhibition of reactivation, but also mechanisms regulating HIV-1 latency in CD4+T memory T cells in general, to expand on “block-and-lock” approaches, and explore alternative options for retroviral suppression. There are approximately 320 human chromatin regulators, which “write”, “erase”, or “read” chromatin modifications, or remodel nucleosome topology. Specificity in gene expression derives from the combinatorial nature of chromatin modifications, and assembly of related chromatin regulator subunits. The rationale for this proposal is that factors that establish HIV-1 latency are important for viral reactivation, and that by identifying and inhibiting them, a “locked” state of silencing that is exceedingly resistant to reactivation can be achieved. We propose to combine a comprehensive high-resolution mapping of the nucleosome organization and positioning of chromatin remodeling complexes at the HIV promoter during HIV latency, with a robust pooled shRNAs screening approach to interrogate all chromatin regulatory factors in parallel during a single experiment. Primary and secondary screens will be performed in a newly developed primary cell system that captures bona fide HIV-1 latency, and departs from CD4+T cells from successfully treated HIV infected donors. During the R61 phase of the project we will be able to correlate high-resolution nucleosome architecture data with their binding to all chromatin remodeling machine families and develop a comprehensive picture of the signals and factors that drive chromatin activity at the HIV-1 genome during latency. This data will support robust hypotheses and targets to test in detail during the R33 phase. We anticipate that from these candidates, we can infer how HIV-latency is controlled and develop rational therapeutic approaches to modulate HIV latency.
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)

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Susana T Valente其他文献

Potent suppression of HIV viral replication by a novel inhibitor of Tat
  • DOI:
    10.1186/1742-4690-9-s1-o11
  • 发表时间:
    2012-05-25
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Guillaume Mousseau;Mark A Clementz;Wendy N Bakeman;Nisha Nagarsheth;Michael Cameron;Jun Shi;Phil Baran;Rémi Fromentin;Nicolas Chomont;Susana T Valente
  • 通讯作者:
    Susana T Valente

Susana T Valente的其他文献

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{{ truncateString('Susana T Valente', 18)}}的其他基金

Development and characterization of HIV-1 Tat degraders
HIV-1 Tat 降解剂的开发和表征
  • 批准号:
    10483950
  • 财政年份:
    2022
  • 资助金额:
    $ 48.74万
  • 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
  • 批准号:
    10516096
  • 财政年份:
    2021
  • 资助金额:
    $ 48.74万
  • 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
  • 批准号:
    10427641
  • 财政年份:
    2021
  • 资助金额:
    $ 48.74万
  • 项目类别:
Validation and characterization of Tat inhibitors identified through HTS
通过 HTS 鉴定的 Tat 抑制剂的验证和表征
  • 批准号:
    10258019
  • 财政年份:
    2021
  • 资助金额:
    $ 48.74万
  • 项目类别:
Validation and characterization of Tat inhibitors identified through HTS
通过 HTS 鉴定的 Tat 抑制剂的验证和表征
  • 批准号:
    10468812
  • 财政年份:
    2021
  • 资助金额:
    $ 48.74万
  • 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
  • 批准号:
    10403317
  • 财政年份:
    2021
  • 资助金额:
    $ 48.74万
  • 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
  • 批准号:
    10591707
  • 财政年份:
    2021
  • 资助金额:
    $ 48.74万
  • 项目类别:
Validation and characterization of Tat inhibitors identified through HTS
通过 HTS 鉴定的 Tat 抑制剂的验证和表征
  • 批准号:
    10591875
  • 财政年份:
    2021
  • 资助金额:
    $ 48.74万
  • 项目类别:
Identification and characterization of chromatin regulators of HIV-1 latency
HIV-1 潜伏期染色质调节因子的鉴定和表征
  • 批准号:
    9975693
  • 财政年份:
    2018
  • 资助金额:
    $ 48.74万
  • 项目类别:
Identification and characterization of chromatin regulators of HIV-1 latency
HIV-1 潜伏期染色质调节因子的鉴定和表征
  • 批准号:
    10591851
  • 财政年份:
    2018
  • 资助金额:
    $ 48.74万
  • 项目类别:

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