Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.
Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, Tennessee, USA.
J Virol. 2020 Oct 27;94(22). doi: 10.1128/JVI.01061-20.
CD4 T-cell depletion is a hallmark of HIV/AIDS, but the underlying mechanism is still unclear. We have recently shown that ataxia-telangiectasia-mutated (ATM) deficiency in CD4 T cells accelerates DNA damage, telomere erosion, and cell apoptosis in HIV-infected individuals on antiretroviral therapy (ART). Whether these alterations in ART-treated HIV subjects occur in HIV-infected CD4 T cells remains unknown. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the telomeric DNA damage response (DDR) and cellular apoptosis in highly permissive SupT1 cells, followed by the validation of our observations in primary CD4 T cells with active or drug-suppressed HIV infection. Specifically, we established an HIV T-cell culture system with viral replication and raltegravir (RAL; an integrase inhibitor) suppression, mimicking active and ART-controlled HIV infection We demonstrated that HIV-induced, telomeric DDR plays a pivotal role in triggering telomere erosion, premature T-cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This model provides a new tool to investigate HIV pathogenesis, and our results shed new light on the molecular mechanisms of telomeric DDR and CD4 T-cell homeostasis during HIV infection. The hallmark of HIV infection is a gradual depletion of CD4 T cells, with a progressive decline of host immunity. How CD4 T cells are depleted in individuals with active and virus-suppressed HIV infection remains unclear. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the chromosome end (telomere) DNA damage response (DDR) and cellular apoptosis in a T-cell line (highly permissive SupT1 cells), as well as in primary CD4 T cells with active or drug-suppressed HIV infection. We demonstrated that HIV-induced telomeric DDR plays a critical role in inducing telomere loss, premature cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This study sheds new light on the molecular mechanisms of telomeric DDR and its role in CD4 T-cell homeostasis during HIV infection.
CD4 T 细胞耗竭是 HIV/AIDS 的一个标志，但潜在的机制仍不清楚。我们最近表明，在接受抗逆转录病毒治疗 (ART) 的 HIV 感染者中，CD4 T 细胞中的共济失调毛细血管扩张突变 (ATM) 缺陷会加速 DNA 损伤、端粒磨损和细胞凋亡。在接受 ART 治疗的 HIV 患者中，这些改变是否发生在 HIV 感染的 CD4 T 细胞中尚不清楚。在这项研究中，我们使用 HIV 感染的细胞模型，通过分析高度易感染的 SupT1 细胞中的端粒 DNA 损伤反应 (DDR) 和细胞凋亡，来研究 CD4 T 细胞破坏的机制，随后在具有活跃或药物抑制性 HIV 感染的原代 CD4 T 细胞中验证我们的观察结果。具体来说，我们建立了一个带有病毒复制和拉替拉韦（RAL；一种整合酶抑制剂）抑制的 HIV T 细胞培养系统，模拟活跃和 ART 控制的 HIV 感染。我们证明了 HIV 诱导的端粒 DDR 通过 PI3K/ATM 途径的失调，在触发端粒磨损、过早的 T 细胞衰老以及 CD4 T 细胞凋亡或耗竭方面发挥关键作用。该模型为研究 HIV 发病机制提供了一种新工具，我们的研究结果为 HIV 感染期间端粒 DDR 和 CD4 T 细胞动态平衡的分子机制提供了新的认识。HIV 感染的标志是 CD4 T 细胞逐渐耗竭，宿主免疫力逐渐下降。在活跃和病毒抑制的 HIV 感染者中，CD4 T 细胞是如何耗竭的仍不清楚。在这项研究中，我们使用 HIV 感染的细胞模型，通过分析 T 细胞系（高度易感染的 SupT1 细胞）和具有活跃或药物抑制性 HIV 感染的原代 CD4 T 细胞中端粒末端（端粒）DNA 损伤反应（DDR）和细胞凋亡，来研究 CD4 T 细胞破坏的机制。我们证明了 HIV 诱导的端粒 DDR 通过 PI3K/ATM 途径的失调，在诱导端粒丢失、过早的细胞衰老以及 CD4 T 细胞凋亡或耗竭方面发挥关键作用。这项研究为端粒 DDR 的分子机制及其在 HIV 感染期间 CD4 T 细胞动态平衡中的作用提供了新的认识。
