Galati Domenico, Bocchino Marialuisa, Paiardini Mirko, Cervasi Barbara, Silvestri Guido, Piedimonte Giuseppe
Dipartimento di Internistica Clinica e Sperimentale F. MAGRASSI, Seconda Università degli Studi di Napoli, Italy.
Curr Drug Targets Immune Endocr Metabol Disord. 2002 Apr;2(1):53-61.
Human immunodeficiency virus (HIV) infection is characterized by a severe depletion of both CD4+ and CD8+ T cells, representing the result of virus-mediated killing of infected lymphocytes and the programmed cell death (apoptosis) of the uninfected bystander cells. Since only a small fraction of T lymphocytes are depleted by viral killing, apoptosis represents one of the most important mechanism of T cell death during HIV infection. Several apoptotic pathways can be triggered by the different stimuli: persistent T lymphocyte activation; altered death receptor (Fas, TNF-R, TRAIL R1-R2) membrane expression; viral proteins as well as gp120, Tat, and Nef; host factors such as the unbalance of cytokine synthesis by lymphocyte. Nevertheless, new evidences have demonstrated that the persistent HIV induced T cell activation and proliferation cause a cell cycle dysregulation resulting in a 5-fold increase in apoptotic cells. This perturbation represents a link between HIV infection, T cell activation, accelerated cell turnover and increased apoptosis and may thus represent a new therapeutic target. In fact, Interleukin-2 administration reverts such a cell cycle dysregulation and reduces activation induced T cell apoptosis. Herein we analyze the main HIV-related mechanisms of host cell death, that are dysregulation of the cell cycle and apoptosis induction of T lymphocytes. Finally, the role of cytokines at the site of infection and their association with apoptosis will be discussed to get insights into the immunological perturbations accounting for an accelerated disease progression. Current therapeutic approaches and strategies, like HAART and recombinant cytokines, that may, successfully, improve the immune-system dysregulation, are also discussed.
人类免疫缺陷病毒（HIV）感染的特征是CD4+和CD8+ T细胞严重耗竭，这是病毒介导的感染淋巴细胞杀伤以及未感染旁观者细胞程序性细胞死亡（凋亡）的结果。由于只有一小部分T淋巴细胞因病毒杀伤而耗竭，凋亡是HIV感染期间T细胞死亡的最重要机制之一。不同刺激可触发多种凋亡途径：持续的T淋巴细胞活化；死亡受体（Fas、TNF-R、TRAIL R1-R2）膜表达改变；病毒蛋白以及gp120、Tat和Nef；宿主因素，如淋巴细胞细胞因子合成失衡。然而，新证据表明，持续的HIV诱导T细胞活化和增殖会导致细胞周期失调，从而使凋亡细胞增加5倍。这种紊乱代表了HIV感染、T细胞活化、加速细胞更新和凋亡增加之间的联系，因此可能代表一个新的治疗靶点。事实上，给予白细胞介素-2可逆转这种细胞周期失调并减少活化诱导的T细胞凋亡。在此，我们分析宿主细胞死亡的主要HIV相关机制，即细胞周期失调和T淋巴细胞凋亡诱导。最后，将讨论感染部位细胞因子的作用及其与凋亡的关联，以深入了解导致疾病加速进展的免疫紊乱。还将讨论当前可能成功改善免疫系统失调的治疗方法和策略，如高效抗逆转录病毒治疗（HAART）和重组细胞因子。
