Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.
Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.
Front Immunol. 2021 May 4;12:658420. doi: 10.3389/fimmu.2021.658420. eCollection 2021.
The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs.
艾滋病毒/艾滋病的标志是 CD4 T 细胞的逐渐耗竭。尽管抗逆转录病毒疗法（ART）的有效控制，但相当一部分艾滋病毒感染者（PLHIV）未能实现完全的免疫重建，被认为是免疫无应答者（INRs）。PLHIV 中不完全的 CD4 T 细胞恢复的机制仍不清楚。在这项研究中，对 PLHIV 的 CD4 T 细胞进行了表型和功能特征分析，重点是它们的线粒体功能。结果表明，虽然总 CD4 T 细胞减少，但 PLHIV 中的循环细胞扩增，尤其是在 INR 中。HIV-INR CD4 T 细胞更活跃，表现出耗尽和衰老的表型，线粒体功能受损。转录谱分析和流式细胞术分析显示，PLHIV 的 CD4 T 细胞中线粒体转录因子 A（mtTFA）显著受抑制，导致线粒体和 T 细胞稳态异常。这些结果表明，T 细胞过度激活、增殖、衰竭、衰老、凋亡和耗竭是一个连续的细胞范例，与受损的线粒体功能相关。因此，重建 mtTFA 途径可能为接受 ART 治疗的 PLHIV 中恢复 CD4 T 细胞提供一种辅助免疫方法，特别是在 INR 中。
