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
• 负责人: Zhi Q. Yao
• 金额: $ 37.5万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10845843
• 关键词: Administrative Supplement; Aging; Apoptosis; Award; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cell Aging; Cell Count; Cell physiology; Development; Disease; Elderly; Eligibility Determination; Epigenetic Process; Exhibits; Funding; Genes; HIV; HIV Infections; HIV antiretroviral; Immune; Immunocompetence; Immunotherapy; Incidence; Infection; Knock-out; Knowledge; Malignant Neoplasms; Measures; Mediating; Messenger RNA; MicroRNAs; Mitochondria; Mitochondrial DNA; Molecular; Morbidity - disease rate; Nerve Degeneration; PPAR gamma; Parents; Participant; Pathogenesis; Patient Care; Patients; Persons; Play; Ploidies; Premature aging syndrome; Process; Production; Proliferating; Proteins; Public Health; Reactive Oxygen Species; Regulation; Repression; Research; Respiration; Role; T-Lymphocyte; Testing; Translating; Translational Research; Untranslated RNA; Veterans; antiretroviral therapy; clinically relevant; differential expression; exhaustion; functional disability; genetic regulatory protein; immune reconstitution; mitochondrial dysfunction; mitochondrial fitness; mortality; mtTF1 transcription factor; novel; overexpression; parent project; peripheral blood; posttranscriptional; premature; programs; reconstitution; senescence; translational study

SUMMARY - Mitochondrial Dysfunction in Aging CD4 T Cells in HIV Immune Non-Responders Despite effective control of HIV by antiretroviral therapy (ART), a significant number of HIV patients fail to achieve complete immune reconstitution and are deemed immune non-responders (INRs). CD4 T cells from these HIV-INRs exhibit prominent mitochondrial dysfunction and premature aging, which play a major role in HIV latency and increase the incidence of non-AIDS, non-communicable diseases (NCDs). To date, how CD4 T cells develop mitochondrial dysfunction and premature aging is unknown, thus raising an urgent need to uncover these molecular processes. The objective of this administrative supplemental proposal is to elucidate the mechanisms that drive mitochondrial dysfunction in aging CD4 T cells during HIV infection. During our parent award entitled “HIV infection- induced mitochondrial dysfunction and premature T cell aging”, our studies revealed significant changes in mitochondrial functions in aging CD4 T cells from HIV patients (especially in INRs), including decreases in mitochondrial respiration, ATP production, and mitochondrial (mt)DNA content, and increases in the synthesis of reactive oxygen species (ROS) and expression of aging markers. Importantly, we found that these functionally impaired, aging CD4 T cells display significant repression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) and mitochondrial transcription factor A (mtTFA) - two mitochondrial master regulators - along with differential expression of specific non-coding RNAs (ncRNAs), which control the expression of target genes at the post-transcriptional level. Based on these new findings, we further hypothesize that mitochondrial regulatory proteins PGC1a and mtTFA are epigenetically dysregulated by ncRNAs during HIV infection, leading to mitochondrial dysfunction and CD4 T cell aging. We propose two aims to test this hypothesis. Aim 1 will investigate how PGC1α and mtTFA are repressed in CD4 T cells during latent HIV infection. Aim 2 will determine the impact of PGC1α and mtTFA repression on CD4 T cell aging during latent HIV infection. This translational research is novel and will answer clinically relevant questions: how HIV infection induces mitochondrial dysfunction and aging in CD4 T cells; and whether targeting the mitochondrial regulatory machinery can restore mitochondrial functions and reprogram the CD4 T cell aging process. Information gained from this study will fill major knowledge gaps in understanding of the pathogenesis of HIV latency and facilitate the development of novel HIV immunotherapy. Thus, this proposal is significant and will have a potentially high impact on HIV and aging research. Because this administrative supplemental application is based on our funded parent project, will add participants (including elderly Veterans) with HIV to our ongoing study where such participants were not enrolled in sufficient numbers to make meaningful comparations between groups for exploration of new measures to elucidate the role and mechanisms of master mitochondrial regulators in T cell mitochondrial regulation, this administrative supplemental application is relevant to HIV and aging research, meets the eligibility criteria, and fits within the scope of our existing award.

摘要 - HIV 免疫无反应者中老化 CD4 T 细胞的线粒体功能障碍 尽管通过抗逆转录病毒疗法（ART）有效控制了艾滋病毒，但仍有大量艾滋病毒患者未能实现目标 完全免疫重建并被视为免疫无反应者 (INR)。来自这些 HIV-INR 的 CD4 T 细胞 表现出明显的线粒体功能障碍和过早衰老，这在艾滋病毒潜伏期和 增加非艾滋病、非传染性疾病 (NCD) 的发病率。迄今为止，CD4 T 细胞是如何发育的 线粒体功能障碍和过早衰老尚不清楚，因此迫切需要揭示这些分子 流程。本行政补充提案的目的是阐明驱动机制 HIV 感染期间老化 CD4 T 细胞的线粒体功能障碍。在我们题为“艾滋病毒感染- 诱导线粒体功能障碍和 T 细胞过早衰老”，我们的研究揭示了 HIV 患者衰老的 CD4 T 细胞中的线粒体功能（尤其是 INR），包括 线粒体呼吸、ATP 产生和线粒体 (mt)DNA 含量，以及合成的增加 活性氧（ROS）和衰老标志物的表达。重要的是，我们发现这些功能 受损、老化的 CD4 T 细胞表现出对过氧化物酶体增殖物激活受体 γ 的显着抑制 共激活因子 1 α (PGC1α) 和线粒体转录因子 A (mtTFA) - 两个线粒体主调节因子 - 以及控制靶标表达的特定非编码 RNA (ncRNA) 的差异表达 转录后水平的基因。基于这些新发现，我们进一步假设线粒体 HIV 感染期间，NCRNA 会导致调节蛋白 PGC1a 和 mtTFA 发生表观遗传失调，从而导致 线粒体功能障碍和 CD4 T 细胞衰老。我们提出两个目标来检验这一假设。目标 1 将进行调查 HIV 潜伏感染期间 CD4 T 细胞中的 PGC1α 和 mtTFA 如何受到抑制。目标 2 将确定影响 PGC1α 和 mtTFA 对潜伏 HIV 感染期间 CD4 T 细胞衰老的抑制。这项转化研究很新颖 并将回答临床相关问题：HIV感染如何诱导CD4线粒体功能障碍和衰老 T细胞；以及针对线粒体调节机制是否可以恢复线粒体功能以及 重新编程 CD4 T 细胞衰老过程。从这项研究中获得的信息将填补以下方面的主要知识空白： 了解艾滋病毒潜伏期的发病机制并促进新型艾滋病毒免疫疗法的开发。因此， 该提案意义重大，将对艾滋病毒和老龄化研究产生潜在的重大影响。因为这个 行政补充申请是在我们资助的母项目的基础上，将增加参与者（包括老年人） 退伍军人）感染艾滋病毒参加我们正在进行的研究，其中这些参与者没有招募足够的数量来进行 各组之间进行有意义的比较，以探索新的措施，以阐明 掌握 T 细胞线粒体调节中的线粒体调节因子，此行政补充申请是 与艾滋病毒和衰老研究相关，符合资格标准，并且符合我们现有奖项的范围。