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免疫非反应器中衰老CD4 T细胞中衰老CD4 T细胞中的密码症功能障碍 尽管通过抗逆转录局（ART）对HIB有效控制，但大量的Hivients无法实现 完全的免疫重组，被视为免疫非反应器（INRS）。 表现出突出的线粒体功能障碍和过早衰老，在艾滋病毒潜伏期中起主要作用 增加非AID，非启动性疾病（NCD）的发病率。 线粒体功能障碍和过早衰老尚不清楚，因此迫切需要发现分子 过程。 HIV感染期间老化CD4 T细胞的线粒体功能障碍。 诱导的mitchondrial功能障碍和过早的T细胞衰老，我们的研究表明 来自HIV患者（尤其是INRS）的老化CD4 T细胞的线粒体功能，包括降低 线粒体呼吸，ATP产生和线粒体（MT）DNA含量，并增加合成 活性氧（ROS）和衰老标记的表达。 受损的，老化的CD4 T细胞显示出明显的过氧化物酶体增殖物激活的受体伽马 共激活因子1α（PGC1α）和线粒体转录因子A（MTTFA） - 两个线粒体主调节剂 - 具有特定非编码RNA（NCRNA）的差异表达，该表达控制靶标的表达 基于转录后的基因。 调节性蛋白PGC1A和MTTFA在居住过程中表观遗传遗传失调，导致 线粒体功能障碍和CD4 T细胞衰老。 在潜在的蜂巢感染过程中，如何在CD4 T细胞中抑制PGC1α和MTTFA。 PGC1α和MTTFA在潜在的HIV感染过程中对CD4 T细胞衰老的抑制作用。 并将回答临床上相关的问题：HIV HIV感染如何在CD4中诱导Mitchondrial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 复制CD4 T细胞老化过程。 因此，对HIV的发病机理的理解是新型HIV免疫疗法的发展 该提案很重要，对艾滋病毒和衰老研究可能会产生很大的影响。 行政补充申请基于我们资助的家长项目，将增加参与者（包括老年人） 退伍军人）接受HIV进行正在进行的研究，在该研究中，此类参与者没有入学 群体之间有意义的比较，以探索新措施，以阐明 T细胞线粒体调节中的线粒体调节剂，此行政补充应用是 与艾滋病毒和老化研究有关，符合符合条件的标准，并符合我们现有奖项的范围。