Mitochondrial Dysfunction in Aging CD4 T cells in HIV-immune Non-responders.

概述-HIV免疫无应答患者中CD4T细胞老化的线粒体功能障碍 尽管通过抗逆转录病毒疗法(ART)有效地控制了艾滋病毒，但相当数量的艾滋病毒患者未能实现 完全免疫重建，被认为是免疫无应答者(INRs)。这些HIV-INRs中的CD4T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、非传染性疾病的发病率。迄今为止，CD4T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。这项行政补充提案的目的是阐明推动 HIV感染过程中老化的CD4T细胞线粒体功能障碍。在我们的父母颁奖典礼上题为“艾滋病毒感染-- 导致线粒体功能障碍和T细胞过早老化“，我们的研究揭示了显著的变化 HIV患者老化的CD4T细胞(特别是INRS)的线粒体功能，包括 线粒体呼吸作用、ATP产生和线粒体(Mt)DNA含量，并增加合成 活性氧(ROS)与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CD4T细胞表现出对过氧化体增殖物激活受体-γ的显著抑制 辅活化子1α(Pgc1α)和线粒体转录因子A(MtTFA)--两种线粒体主调控因子 -以及控制靶基因表达的特定非编码RNA(NcRNAs)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 在HIV感染过程中，调控蛋白PGC1a和mtTFA受到ncRNAs的表观遗传失调，导致 线粒体功能障碍与CD4T细胞老化。我们提出了两个目的来检验这一假设。AIM 1将调查 潜伏感染HIV过程中CD4T细胞pGC1mtTFA和α的表达目标2将确定 前列环素α和mtTFA对潜伏感染时CD4T细胞老化的抑制作用这项翻译研究是新颖的。 并将回答与临床相关的问题：HIV感染如何导致CD4中线粒体功能障碍和衰老 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和 对CD4T细胞老化过程进行重新编程。这项研究获得的信息将填补以下方面的主要知识空白 了解HIV潜伏期的发病机制，有助于开发新型的HIV免疫疗法。因此， 这项提议意义重大，并将对艾滋病毒和老龄化研究产生潜在的高度影响。因为这件事 行政补充申请是基于我们资助的家长项目，将增加参与者(包括老年人 在我们正在进行的研究中，这些参与者的登记人数不足以使 小组之间有意义的比较，以探索新的措施，以阐明的作用和机制 掌握线粒体调节剂对T细胞线粒体的调节，这一行政补充应用是 与艾滋病毒和老龄化研究相关，符合资格标准，符合我们现有奖项的范围。

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.