HIV infection-induced mitochondrial dysfunction and premature T cell aging

HIV感染引起的线粒体功能障碍和T细胞过早衰老

基本信息

  • 批准号:
    10203459
  • 负责人:
  • 金额:
    $ 42.76万
  • 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:
    2021-09-05 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

HIV infection-induced mitochondrial dysfunction and premature T cell aging HIV infection appears to drive premature T cell aging, evidenced by mitochondrial dysfunction. How CD4 T cells develop mitochondrial dysfunction during HIV infections is unclear. The objective of this proposal is to elucidate the mechanisms of mitochondrial dysfunction during chronic HIV infection, so as to develop effective means to rescue CD4 T cell depletion or functional impairment, the sine que non of HIV-infection. To elucidate the mechanisms underlying mitochondrial dysfunction in CD4 T cell aging, we analyzed the mitochondrial function of CD4 T cells derived from ART-controlled HIV patients. Our preliminary data show that HIV CD4 T cells have decreased mitochondrial DNA (mtDNA) content, mitochondrial respiration, and ATP production. To identify candidate proteins involved in dysregulating mtDNA copy numbers, we performed Liquid Chromatography Mass Spectrometry (LC-MS) on purified mitochondria from CD4 T cells of HIV patients and health subjects (HS). We found largest reduction of mitochondrial proteins (SOD1 and PRDX1) in destroying reactive oxygen species (ROS), and in repair of ROS- mediated DNA damage repair (APEX1), and elevation of proteins in mtDNA degrading (EXOG and ENDOG) and mtDNA replication (POLG and MGME1). Based on these and other preliminary data, we hypothesize that ROS- mediated mtDNA damage (via lower SOD1 and/or PDRX1 and APEX1) may cause higher mtDNA degradation (by EXOG and ENDOG), which may not be sufficiently complemented by mtDNA replication (through higher POLG and MGME1), leading to lower mtDNA copy number and impaired mitochondrial functions that we have seen in HIV- derived CD4 T cells. We propose two aims to define the mechanisms leading to mtDNA decrease and compromised function. In Aim 1, We will determine if ectopic expression of SOD1 and/or PRDX1 can reduce ROS level and oxidative mtDNA damage in CD4 T cells of HIV patients. In addition, ectopic expression of APEX1 will be performed to determine the involvement of APEX1 in repairing damaged mtDNA via the base excision repair (BER) pathway. siRNA knockdown of SOD1 and/or PRDX1, and APEX1 will also be performed in healthy CD4 T cells to confirm their roles in mtDNA damage and copy number maintenance, mitochondrial respiration, and ATP production. In Aim 2, we will use transient siRNA knockdown or Crisper/Cas9 knockout to reduce the EXOG and/or ENDOG nucleases in CD4 T cells from HIV patients, and to assess the levels of oxidative mtDNA damage and rescue of mtDNA copy number. We will perform single molecule analysis of replicated DNA (SMARD) on mtDNA in cultured CD4 T cells from HIV patients to comprehensively assess the status of mtDNA replication in response to T cell receptor (TCR) stimulation. Overall, this application is novel and strong in both concept and approach to answer clinically relevant questions: how chronic viral infection induces mitochondrial dysfunction, leading to premature T cells aging, and whether interfering those over-activated enzymes responsible for mtDNA copy number reduction and mitochondrial dysfunction can remodel T cell aging and function during HIV infection. Understanding such mechanisms is critical for developing approaches to improve immune responses in the setting of many infectious or inflammatory diseases.
HIV infection-induced mitochondrial dysfunction and premature T cell aging HIV infection appears to drive premature T cell aging, evidenced by mitochondrial dysfunction. How CD4 T cells develop mitochondrial dysfunction during HIV infections is unclear. The objective of this proposal is to elucidate the mechanisms of mitochondrial dysfunction during chronic HIV infection, so as to develop effective means to rescue CD4 T cell depletion or functional impairment, the sine que non of HIV-infection. To elucidate the mechanisms underlying mitochondrial dysfunction in CD4 T cell aging, we analyzed the mitochondrial function of CD4 T cells derived from ART-controlled HIV patients. Our preliminary data show that HIV CD4 T cells have decreased mitochondrial DNA (mtDNA) content, mitochondrial respiration, and ATP production. To identify candidate proteins involved in dysregulating mtDNA copy numbers, we performed Liquid Chromatography Mass Spectrometry (LC-MS) on purified mitochondria from CD4 T cells of HIV patients and health subjects (HS). We found largest reduction of mitochondrial proteins (SOD1 and PRDX1) in destroying reactive oxygen species (ROS), and in repair of ROS- mediated DNA damage repair (APEX1), and elevation of proteins in mtDNA degrading (EXOG and ENDOG) and mtDNA replication (POLG and MGME1). Based on these and other preliminary data, we hypothesize that ROS- mediated mtDNA damage (via lower SOD1 and/or PDRX1 and APEX1) may cause higher mtDNA degradation (by EXOG and ENDOG), which may not be sufficiently complemented by mtDNA replication (through higher POLG and MGME1), leading to lower mtDNA copy number and impaired mitochondrial functions that we have seen in HIV- derived CD4 T cells. We propose two aims to define the mechanisms leading to mtDNA decrease and compromised function. In Aim 1, We will determine if ectopic expression of SOD1 and/or PRDX1 can reduce ROS level and oxidative mtDNA damage in CD4 T cells of HIV patients. In addition, ectopic expression of APEX1 will be performed to determine the involvement of APEX1 in repairing damaged mtDNA via the base excision repair (BER) pathway. siRNA knockdown of SOD1 and/or PRDX1, and APEX1 will also be performed in healthy CD4 T cells to confirm their roles in mtDNA damage and copy number maintenance, mitochondrial respiration, and ATP production. In Aim 2, we will use transient siRNA knockdown or Crisper/Cas9 knockout to reduce the EXOG and/or ENDOG nucleases in CD4 T cells from HIV patients, and to assess the levels of oxidative mtDNA damage and rescue of mtDNA copy number. We will perform single molecule analysis of replicated DNA (SMARD) on mtDNA in cultured CD4 T cells from HIV patients to comprehensively assess the status of mtDNA replication in response to T cell receptor (TCR) stimulation. Overall, this application is novel and strong in both concept and approach to answer clinically relevant questions: how chronic viral infection induces mitochondrial dysfunction, leading to premature T cells aging, and whether interfering those over-activated enzymes responsible for mtDNA copy number reduction and mitochondrial dysfunction can remodel T cell aging and function during HIV infection. Understanding such mechanisms is critical for developing approaches to improve immune responses in the setting of many infectious or inflammatory diseases.

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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Zhi Q. Yao其他文献

Zhi Q. Yao的其他文献

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{{ truncateString('Zhi Q. Yao', 18)}}的其他基金

Dual specific gene editing drugs delivered by nanoparticles targeting HBV/HIV coinfection
针对 HBV/HIV 双重感染的纳米颗粒递送的双特异性基因编辑药物
  • 批准号:
    10403587
  • 财政年份:
    2021
  • 资助金额:
    $ 42.76万
  • 项目类别:
Mitochondrial Dysfunction in Aging CD4 T cells in HIV-immune Non-responders.
HIV 免疫无反应者中衰老 CD4 T 细胞的线粒体功能障碍。
  • 批准号:
    10845843
  • 财政年份:
    2021
  • 资助金额:
    $ 42.76万
  • 项目类别:
Dual specific gene editing drugs delivered by nanoparticles targeting HBV/HIV coinfection
针对 HBV/HIV 双重感染的纳米颗粒递送的双特异性基因编辑药物
  • 批准号:
    10161447
  • 财政年份:
    2021
  • 资助金额:
    $ 42.76万
  • 项目类别:
Multiuser Advanced Confocal Microscope
多用户高级共焦显微镜
  • 批准号:
    9791445
  • 财政年份:
    2019
  • 资助金额:
    $ 42.76万
  • 项目类别:
Telomere loss and T cell aging in HBV vaccine response in HCV-infected individual
HCV 感染者的 HBV 疫苗反应中的端粒丢失和 T 细胞老化
  • 批准号:
    10265317
  • 财政年份:
    2019
  • 资助金额:
    $ 42.76万
  • 项目类别:
Telomere loss and T cell aging in HBV vaccine response in HCV-infected individual
HCV 感染者的 HBV 疫苗反应中的端粒丢失和 T 细胞老化
  • 批准号:
    10455526
  • 财政年份:
    2019
  • 资助金额:
    $ 42.76万
  • 项目类别:
Gender difference in miRNA-mediated T cell aging during viral infection
病毒感染期间 miRNA 介导的 T 细胞衰老的性别差异
  • 批准号:
    9896225
  • 财政年份:
    2019
  • 资助金额:
    $ 42.76万
  • 项目类别:
Premature T cell aging and vaccine failure in chronic viral infection
慢性病毒感染中 T 细胞过早衰老和疫苗失败
  • 批准号:
    9023117
  • 财政年份:
    2016
  • 资助金额:
    $ 42.76万
  • 项目类别:
ShEEP Proposal for a Multiuser Advanced Biosafe Flow Cytometer
ShEEP 针对多用户高级生物安全流式细胞仪的提案
  • 批准号:
    9211532
  • 财政年份:
    2016
  • 资助金额:
    $ 42.76万
  • 项目类别:
Telomere attrition and T cell aging in vaccine failure during HIV infection
HIV 感染期间疫苗失败时的端粒磨损和 T 细胞老化
  • 批准号:
    10581156
  • 财政年份:
    2016
  • 资助金额:
    $ 42.76万
  • 项目类别:
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