Genetic analysis of unspliced HIV RNA produced during HDAC inhibitor therapy

HDAC 抑制剂治疗期间产生的未剪接 HIV RNA 的遗传分析

基本信息

  • 批准号:
    8730254
  • 负责人:
  • 金额:
    $ 15.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-03-01 至 2016-02-28
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Current antiretroviral therapy effectively suppresses but does not eradicate HIV-1 infection. During combination antiretroviral therapy (cART), reduction of HIV-1 RNA levels to less than 50 copies/ml is frequently achieved; however, persistent low-level viremia has been detected in plasma using ultrasensitive assays. The source and dynamics of this persistent viremia is currently under investigation. One well-defined reservoir of HIV-1 is memory CD4+ T cells, where HIV-1 latency is established when an activated CD4+ T cell becomes infected by HIV-1 but transitions to a terminally differentiated memory T cell instead of undergoing lytic infection. Upregulating cellular transcription to induce HIV gene expression has been proposed as a strategy for reducing the pool of latently- infected resting memory CD4+ T cells and possibly myeloid cells carrying an integrated form of the viral genome. This includes inhibiting cellular histone deacetylases (HDACs) because these HDACs promote latency by regulating genome structure and transcriptional activity. A recent treatment of eight HIV-infected patients on suppressive cART with a single dose of the histone deacetylase inhibitor (HDACi), vorinostat, resulted in a significant increase in cell associated unspliced (CA-US) HIV RNA in resting memory CD4+ T cells. During a clinical trial in Australia, a similar significant increase in CA- US HIV RNA was observed in CD4+ T-cells in blood from HIV-infected patients treated with 14 days of the HDACi vorinostat. Preliminary data from a multidose study of the HDACi panobinostat in Denmark also demonstrates an increase in CA-US HIV RNA. Given these findings, we hypothesize that: 1) the sequence of CA-US HIV RNA following HDACi treatment will be clonal which is consistent with transcription from a subset of infected resting memory T cells responsive to HDAC inhibitors in the blood and gut; 2) specific cell types are producing CA-US HIV RNA; 3) this CA-US HIV RNA will be genetically similar to pre-therapy (pre-cART and pre-HDACi) plasma-derived HIV-1 sequences, indicating this reservoir was established prior to cART initiation; 4) if virus rebounds during an analytical treatment interruption post-panobinostat therapy, it will be genetically similar to CA-US HIV RNA reactivated during HDACi therapy. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) to determine the genetic makeup and diversity of CA-US HIV RNA from CD4+ T cells of patients prior to and following multi- dose treatment with vorinostat or panobinostat; (2) to determine the genetic makeup and diversity of unspliced HIV-1 RNA in myeloid cells and specific memory CD4+ T cell subsets; and (3) to compare the genetic makeup of CA-US HIV RNA to plasma-derived HIV-1 sequences from pre-therapy samples and samples taken after an analytical treatment interruption following panobinostat therapy. If this exploratory study reveals clonal expansion of CA-US HIV RNA in myeloid cells and specific resting memory T cells from HIV-1 infected patients on HDAC inhibitors, this would provide direct evidence that these compounds are disrupting proviral latency within these cells and that HIV latency can be therapeutically targeted in humans.
项目总结

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Sarah Elizabeth Palmer其他文献

Sarah Elizabeth Palmer的其他文献

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{{ truncateString('Sarah Elizabeth Palmer', 18)}}的其他基金

Combining immunogenic peptides and Nef blockade to enhance CD8 T-cell-mediated clearance of HIV-infected cells
结合免疫原性肽和 Nef 阻断来增强 CD8 T 细胞介导的 HIV 感染细胞清除
  • 批准号:
    10685405
  • 财政年份:
    2022
  • 资助金额:
    $ 15.66万
  • 项目类别:
Combining immunogenic peptides and Nef blockade to enhance CD8 T-cell-mediated clearance of HIV-infected cells
结合免疫原性肽和 Nef 阻断来增强 CD8 T 细胞介导的 HIV 感染细胞清除
  • 批准号:
    10482443
  • 财政年份:
    2022
  • 资助金额:
    $ 15.66万
  • 项目类别:
Viral reservoirs and sanctuaries in HAART - treated patients: role and mechanisms
HAART 治疗患者中的病毒库和庇护所:作用和机制
  • 批准号:
    8202570
  • 财政年份:
    2011
  • 资助金额:
    $ 15.66万
  • 项目类别:
Targeting_the_Source_of_Persistent_HIV_Viremia
持续性 HIV 病毒血症的目标来源
  • 批准号:
    8047422
  • 财政年份:
    2010
  • 资助金额:
    $ 15.66万
  • 项目类别:
Viral reservoirs and sanctuaries in HAART - treated patients: role and mechanisms
HAART 治疗患者中的病毒库和庇护所:作用和机制
  • 批准号:
    8500171
  • 财政年份:
  • 资助金额:
    $ 15.66万
  • 项目类别:
Viral reservoirs and sanctuaries in HAART - treated patients: role and mechanisms
HAART 治疗患者中的病毒库和庇护所:作用和机制
  • 批准号:
    8376036
  • 财政年份:
  • 资助金额:
    $ 15.66万
  • 项目类别:
Viral reservoirs and sanctuaries in HAART - treated patients: role and mechanisms
HAART 治疗患者中的病毒库和庇护所:作用和机制
  • 批准号:
    8892978
  • 财政年份:
  • 资助金额:
    $ 15.66万
  • 项目类别:
Viral reservoirs and sanctuaries in HAART - treated patients: role and mechanisms
HAART 治疗患者中的病毒库和庇护所:作用和机制
  • 批准号:
    8703600
  • 财政年份:
  • 资助金额:
    $ 15.66万
  • 项目类别:

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