Fate of Invisible U/A Base Pairs Within HIV DNA in Myeloid Phagocytic Cells

骨髓吞噬细胞中 HIV DNA 中看不见的 U/A 碱基对的命运

基本信息

  • 批准号:
    9138025
  • 负责人:
  • 金额:
    $ 40.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-07-01 至 2021-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): We have delineated the elements of a novel HIV-1 restriction/persistence mechanism that operates solely within the unique intracellular environment of bone marrow-derived monocytes (MCs) and monocyte-derived macrophages (MDMs), but not resting or activated T cells. The mechanism centers on the high concentration of dUTP in MCs and MDMs, which forces reverse transcriptase (RTase) to incorporate dUMP opposite to adenine during reverse transcription, leading to high levels of U/A base pairs ("uracilation"). Importantly, U/A pairs do not perturb the coding sequence and are invisible to standard DNA sequencing methods because U reads as T. However, U/A pairs are a substrate for the host uracil base excision repair (UBER) machinery, which modulates the outcome of HIV infection in these cells. Uracilation and UBER impact HIV infection of macrophages in diverse ways. First, potent pre- integration restriction occurs by uracil excision and viral DNA fragmentation. Proviruses that escape initial restriction contain U/A pairs that can persist, resulting in uracil- induced silencing of HIV-1 gene expression. Upon stimulation of infected MDMs with pro-inflammatory cytokines, otherwise stable uracilated proviruses become heavily mutagenized through error-prone UBER, suggesting that the M1/M2 polarization state of the macrophage can determine the fate viral uracils. Low levels of infectious virus can emerge from uracilated proviruses even after many weeks. In three aims we seek to (i) Elucidate the impact of the UBER pathway in HIV infection of macrophages and MCs. (ii) Determine the effects of U/A base pairs on HIV LTR-driven transcription in MDMs, and (iii) Use the time frame for uracil removal and its characteristic mutagenic signature to determine whether proviruses that have been previously detected in short-lived circulating MCs in HIV infected patients on cART originate from their contact with infected macrophages in various tissues. The elucidation of the role of host UBER in viral infections of macrophages and monocytes is expected to uncover new host drug targets for combating HIV establishment and persistence in these unique immune cells. This proposal brings together clinicians and basic scientists with broad and highly complementary backgrounds in immunology, HIV latency, uracil DNA repair and in obtaining alveolar macrophages from bronchial lavage of HIV-infected volunteers.


项目成果

期刊论文数量(0)
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JAMES T. STIVERS其他文献

JAMES T. STIVERS的其他文献

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{{ truncateString('JAMES T. STIVERS', 18)}}的其他基金

Discovery of Chemical Probes of SAMHD1 for Modulation of Cancer Therapy and the Immune System
发现用于调节癌症治疗和免疫系统的 SAMHD1 化学探针
  • 批准号:
    10163140
  • 财政年份:
    2020
  • 资助金额:
    $ 40.15万
  • 项目类别:
Discovery of Chemical Probes of SAMHD1 for Modulation of Cancer Therapy and the Immune System
发现用于调节癌症治疗和免疫系统的 SAMHD1 化学探针
  • 批准号:
    10396629
  • 财政年份:
    2020
  • 资助金额:
    $ 40.15万
  • 项目类别:
Discovery of Chemical Probes of SAMHD1 for Modulation of Cancer Therapy and the Immune System
发现用于调节癌症治疗和免疫系统的 SAMHD1 化学探针
  • 批准号:
    10650716
  • 财政年份:
    2020
  • 资助金额:
    $ 40.15万
  • 项目类别:
Persistence and Fate of Invisible U/A Pairs in HIV-1 Proviral DNA
HIV-1 前病毒 DNA 中隐形 U/A 对的持久性和命运
  • 批准号:
    8790165
  • 财政年份:
    2014
  • 资助金额:
    $ 40.15万
  • 项目类别:
Persistence and Fate of Invisible U/A Pairs in HIV-1 Proviral DNA
HIV-1 前病毒 DNA 中隐形 U/A 对的持久性和命运
  • 批准号:
    8910622
  • 财政年份:
    2014
  • 资助金额:
    $ 40.15万
  • 项目类别:
Purchase of a 600 MHz NMR Console and Probes
购买 600 MHz NMR 控制台和探头
  • 批准号:
    8051342
  • 财政年份:
    2011
  • 资助金额:
    $ 40.15万
  • 项目类别:
Fluorescence-Based Screen for Human DNA 5-Cytosine-methyltransferase 1
基于荧光的人类 DNA 5-胞嘧啶甲基转移酶 1 筛选
  • 批准号:
    8089372
  • 财政年份:
    2010
  • 资助金额:
    $ 40.15万
  • 项目类别:
Fluorescence-Based Screen for Human DNA 5-Cytosine-methyltransferase 1
基于荧光的人类 DNA 5-胞嘧啶甲基转移酶 1 筛选
  • 批准号:
    8010339
  • 财政年份:
    2010
  • 资助金额:
    $ 40.15万
  • 项目类别:
High Throughput Assay:Topoisomerase Enzyme Targets (RMI)
高通量检测:拓扑异构酶靶标 (RMI)
  • 批准号:
    7022489
  • 财政年份:
    2005
  • 资助金额:
    $ 40.15万
  • 项目类别:
Mechanistic Biology of Topoisomerase 1B
拓扑异构酶 1B 的机制生物学
  • 批准号:
    6890397
  • 财政年份:
    2003
  • 资助金额:
    $ 40.15万
  • 项目类别:

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腺嘌呤核苷酸转位酶在慢性阻塞性肺病(COPD)线粒体功能相关衰老中的作用
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健康老龄化和阿尔茨海默病脑细胞 DNA 腺嘌呤甲基化的批判性评估
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胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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