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.

总结-HIV免疫无应答者中老化CD 4 T细胞的线粒体功能障碍 尽管抗逆转录病毒疗法（ART）有效地控制了艾滋病毒，但仍有相当多的艾滋病毒患者未能达到预期效果。 完全免疫重建，并被视为免疫无应答者（INR）。来自这些HIV-INR的CD 4 T细胞 表现出明显的线粒体功能障碍和过早衰老，这在HIV潜伏期中起着重要作用， 增加非艾滋病、非传染性疾病的发病率。到目前为止，CD 4 T细胞是如何发育的 线粒体功能障碍和过早衰老是未知的，因此迫切需要揭示这些分子 流程.本行政补充建议的目的是阐明驱动 在HIV感染期间老化的CD 4 T细胞的线粒体功能障碍。在我们的父母奖题为“艾滋病毒感染- 诱导的线粒体功能障碍和过早的T细胞老化”，我们的研究揭示了 来自HIV患者的老化CD 4 T细胞中的线粒体功能（特别是在INR中），包括 线粒体呼吸、ATP产生和线粒体（mt）DNA含量，以及 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CD 4 T细胞显示出对过氧化物酶体增殖物激活受体-γ的显著抑制 辅激活因子1 α（PGC 1 α）和线粒体转录因子A（mtTFA）-两种线粒体主调节因子 - 沿着特异性非编码RNA（ncRNA）的差异表达，其控制靶基因的表达， 基因在转录后水平。基于这些新的发现，我们进一步假设， 调节蛋白PGC 1a和mtTFA在HIV感染期间被ncRNA表观遗传失调，导致 线粒体功能障碍和CD 4 T细胞老化。我们提出两个目标来检验这一假设。目标1将调查 在潜伏性HIV感染期间，PGC 1 α和mtTFA在CD 4 T细胞中如何受到抑制。目标2将决定 PGC 1 α和mtTFA对HIV潜伏感染时CD 4 T细胞老化的抑制作用这种转化研究是新颖的 并将回答临床相关的问题：艾滋病毒感染如何诱导线粒体功能障碍和衰老的CD 4 T细胞;以及靶向线粒体调节机制是否可以恢复线粒体功能， 重新编程CD 4 T细胞老化过程。从这项研究中获得的信息将填补主要的知识空白， 了解HIV潜伏期的发病机制，促进新型HIV免疫疗法的发展。因此，在本发明中， 这一建议意义重大，并将对艾滋病毒和老龄化研究产生潜在的重大影响。因为这 行政补充申请是基于我们资助的母项目，将增加参与者（包括老年人 我们正在进行的研究中，这些参与者没有足够的人数参加， 组间有意义的比较，以探索新的措施来阐明的作用和机制， 掌握T细胞线粒体调控中的线粒体调节因子，本行政补充申请是 与艾滋病毒和老龄化研究相关，符合资格标准，并符合我们现有奖项的范围。