Effect of Cdk inhibitor on HIV-1 replication

Cdk 抑制剂对 HIV-1 复制的影响

基本信息

  • 批准号:
    7230046
  • 负责人:
  • 金额:
    $ 18.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-03-01 至 2009-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): There are currently 40-100 million individuals in the world infected with human immunodeficiency virus (HIV), and nearly 16,000 new infections occur worldwide each day based on World Health Organization estimates. The introduction of highly active anti-retroviral therapy (HAART) has led to a significant reduction in AIDS-related morbidity and mortality. Unfortunately, up to 25% of patients discontinue their initial HAART regimen because of treatment failure (inability to suppress HIV viral replication to below the current limit of detection, 50 copies/mL), toxic effects or non-compliance within the first few months of therapy. Therefore, today it is widely believed that the success in HIV-1 treatment will require targeting of other HIV and/or host cellular proteins. The pathogenesis of HIV -induced disease is complex and multifactoral. Several key HIV and cellular proteins have been assigned to be necessary for the course of infection including the transactivator Tat. Viral clones deficient in Tat will not replicate in vitro or in vivo to high liters. Also, cellular activation (a process where cells go from G0 to the Gi/S stage of the cell cycle) of latently infected cells by various stimuli leads to viral expression followed by progeny formation. Minimal activated transcription from the HIV-1 long terminal repeat (LTR) occurs in GO quiescent cells. We previously have shown that HIV-1 in latently infected cells can down modulate the natural cyclin dependent kinase (cdk) inhibitors, and in turn is able to control the primary cdk targets such as cdk2/cyclin E complex. Therefore, inhibition of the Gi/S kinases, could be a possible target for inhibition of HIV-1 replication. More importantly, cdk2 and cyclin E are not essential for the growth of normal (as seen in cdk2"" or cyclin E'A mice), non-cancerous cells, and therefore, use of inhibitors against the cdk2/cyclin E complex may pose a viable option to inhibit HIV-1 in infected cells. Our current preliminary data indicates that cdk2/cyclin E could phosphorylate the RNA Pol IICTD, can be found in the HIV- 1 elongation complexes, recombinant cdk2/cyclin E stimulates Tat-dependent HIV-1 transcription in a reconstituted transcription assay and immunodepletion of cdk2/cyclin E from nuclear extracts blocks Tat-dependent transcription. Also, RNAi experiments show that cdk2 downregulation affects HIV-1, but not HTLV-1, CMV, or IgH promoters. Here, we propose to use an ATP analog and a new derivative which can inhibit cdk activity. The target of these drugs in HIV-1 infected cells is the cdk2/cyclin E complex at an IC50 of 0.009-0.15 uM. Our specific aims include: Aim 1: Effect of CYC202 and its derivative on HIV-1 elongation factor occupancy and splicing. To define the mechanism of inhibition, transcription elongation factor occupancy in presence of drugs will be tested in vivo using ChIP assays. The effect of CYC202 and its derivative on HIV-1 singly or multiply spliced messages will be evaluated in vitro and in vivo using HIV-rtTA (KWK and KYK), PBMCs and Tat variants (wild type, C22G, and L43A). Aim 2: Effect of CYC202 and its derivative compound #4 on HIV-1 variants, and possible cell toxicity. Effect of drug treatment on HIV-1 variants will be tested in wild type and recombinant viruses as well as LTR and Tat transfections. Determine any significant alterations in cellular gene expression following CYC202 or derivative #4 treatments using Microarrays. Therefore, the current proposal is aimed at determining whether drugs such as ATP analogs are a viable option in treating HIV-1 infected cells both in vitro and in vivo.
描述(由申请人提供):目前世界上有4000 -1亿人感染了人类免疫缺陷病毒(HIV),根据世界卫生组织的估计,全世界每天有近16,000个新感染病例。采用高活性抗逆转录病毒疗法(HAART)大大降低了与艾滋病有关的发病率和死亡率。不幸的是,多达25%的患者由于治疗失败(无法将HIV病毒复制抑制到目前的检测极限,50拷贝/mL以下)、毒性作用或在治疗的最初几个月内不依从性而停止了最初的HAART治疗方案。因此,今天人们普遍认为,HIV-1治疗的成功将需要靶向其他HIV和/或宿主细胞蛋白。HIV诱发疾病的发病机制是复杂的、多因素的。几个关键的HIV和细胞蛋白被指定为感染过程所必需的,包括反激活子Tat。缺乏Tat的病毒克隆不会在体外或体内复制到高升。此外,潜伏感染细胞在各种刺激下的细胞活化(细胞从G0阶段进入细胞周期的Gi/S阶段的过程)导致病毒表达,随后是后代的形成。来自HIV-1长末端重复序列(LTR)的最小激活转录发生在氧化石墨烯静止细胞中。我们之前已经证明潜伏感染细胞中的HIV-1可以下调天然细胞周期蛋白依赖性激酶(cdk)抑制剂,进而能够控制cdk2/周期蛋白E复合物等主要cdk靶点。因此,抑制Gi/S激酶可能是抑制HIV-1复制的可能靶点。更重要的是,cdk2和cyclin E对于正常(如cdk2或cyclin E'A小鼠)、非癌细胞的生长不是必需的,因此,使用针对cdk2/cyclin E复合物的抑制剂可能是抑制感染细胞中HIV-1的可行选择。我们目前的初步数据表明,cdk2/cyclin E可以磷酸化RNA Pol IICTD,可以在HIV-1延伸复合物中发现,重组cdk2/cyclin E在重组转录试验中刺激tat依赖性HIV-1转录,从核提取物中免疫缺失cdk2/cyclin E阻断tat依赖性转录。此外,RNAi实验表明cdk2下调影响HIV-1,但不影响HTLV-1、CMV或IgH启动子。在这里,我们建议使用ATP类似物和一种新的衍生物来抑制cdk活性。这些药物在HIV-1感染细胞中的靶点是cdk2/cyclin E复合物,IC50为0.009-0.15 uM。我们的具体目标包括:目标1:CYC202及其衍生物对HIV-1延伸因子占用和剪接的影响。为了确定抑制的机制,转录延伸因子占用存在的药物将在体内使用芯片检测。CYC202及其衍生物对HIV-1单剪接或多剪接信息的影响将在体外和体内使用HIV-rtTA (KWK和KYK)、PBMCs和Tat变体(野生型、C22G和L43A)进行评估。目的2:CYC202及其衍生物化合物#4对HIV-1变异的影响,以及可能的细胞毒性。药物治疗对HIV-1变异的影响将在野生型和重组病毒以及LTR和Tat转染中进行测试。使用微阵列检测CYC202或衍生物#4处理后细胞基因表达的任何显著变化。因此,目前的建议旨在确定ATP类似物等药物是否在体外和体内治疗HIV-1感染细胞的可行选择。

项目成果

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Fatah Kashanchi其他文献

Fatah Kashanchi的其他文献

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{{ truncateString('Fatah Kashanchi', 18)}}的其他基金

American Society for Intercellular Communication (ASIC)
美国细胞间通讯学会 (ASIC)
  • 批准号:
    10753704
  • 财政年份:
    2023
  • 资助金额:
    $ 18.57万
  • 项目类别:
Cell-derived extracellular vesicle mediated epigenetic silencing of HIV in the brain
细胞源性细胞外囊泡介导大脑中HIV的表观遗传沉默
  • 批准号:
    10748545
  • 财政年份:
    2023
  • 资助金额:
    $ 18.57万
  • 项目类别:
American Society for Intercellular Communication (ASIC)
美国细胞间通讯学会 (ASIC)
  • 批准号:
    10539845
  • 财政年份:
    2022
  • 资助金额:
    $ 18.57万
  • 项目类别:
Effect on CBD on Exosome release from CNS infected cells
CBD 对中枢神经系统感染细胞外泌体释放的影响
  • 批准号:
    9884894
  • 财政年份:
    2020
  • 资助金额:
    $ 18.57万
  • 项目类别:
Role of extracellular vesicles in methamphetamine and HIV induced neurotoxicity
细胞外囊泡在甲基苯丙胺和 HIV 诱导的神经毒性中的作用
  • 批准号:
    9929090
  • 财政年份:
    2018
  • 资助金额:
    $ 18.57万
  • 项目类别:
A radiation-induced cellular stress activates HIV and induces killing of infected cells
辐射引起的细胞应激会激活艾滋病毒并诱导杀死受感染的细胞
  • 批准号:
    9326140
  • 财政年份:
    2016
  • 资助金额:
    $ 18.57万
  • 项目类别:
HIV neuropathogenesis related to exosomes containing HIV non-coding RNAs
与含有 HIV 非编码 RNA 的外泌体相关的 HIV 神经发病机制
  • 批准号:
    9136536
  • 财政年份:
    2016
  • 资助金额:
    $ 18.57万
  • 项目类别:
HIV neuropathogenesis related to exosomes containing HIV non-coding RNAs
与含有 HIV 非编码 RNA 的外泌体相关的 HIV 神经发病机制
  • 批准号:
    9893927
  • 财政年份:
    2016
  • 资助金额:
    $ 18.57万
  • 项目类别:
A radiation-induced cellular stress activates HIV and induces killing of infected cells
辐射引起的细胞应激会激活艾滋病毒并诱导杀死受感染的细胞
  • 批准号:
    9212863
  • 财政年份:
    2016
  • 资助金额:
    $ 18.57万
  • 项目类别:
Effect of novel cdk9 inhibitor on HIV transcription
新型cdk9抑制剂对HIV转录的影响
  • 批准号:
    8793029
  • 财政年份:
    2014
  • 资助金额:
    $ 18.57万
  • 项目类别:

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