Aquaro S, Panti S, Caroleo M C, Balestra E, Cenci A, Forbici F, Ippolito G, Mastino A, Testi R, Mollace V, Caliò R, Perno C F
Department of Experimental Medicine, University of Rome Tor Vergata, Italy.
J Leukoc Biol. 2000 Sep;68(3):429-35.
Infection of macrophages (M/M) by human immunodeficiency virus (HIV) is a main pathogenetic event leading to neuronal dysfunction and death in patients with AIDS dementia complex. Alteration of viability of neurons and astrocytes occurs in vivo even without their infection, thus it is conceivable that HIV-infected M/M may affect viability of such cells even without direct infection. To assess this hypothesis, we studied the effects of HIV-infected M/M on an astrocytic cell-line lacking CD4-receptor expression. Exposure to supernatants of HIV-infected M/M triggers complete disruption and apoptotic death of astrocytic cells. This effect is not related to HIV transmission from infected M/M, because HIV-DNA and p24 production in astrocytic cells remained negative. Apoptotic death of astrocytes is mainly mediated by Fas ligand released in supernatants of HIV-infected M/M (as demonstrated by complete reversal of such phenomenon by adding neutralizing antibodies against CD95 receptor). Treatment of astrocytic cells with recombinant (biologically active) Tat induces < 10% apoptosis, and gp120 was totally ineffective. Treatment of HIV-infected M/M with AZT completely reverses the proapoptotic effect of their supernatants on astrocytes, thus demonstrating that productive virus replication within M/M is required for the induction of astrocytic cell death. Taken together, data suggest that homeostasis of astrocytes may be affected by HIV-infected M/M in the absence of productive infection of target cells. This phenomenon may help to explain the cellular damage found in HIV-infected patients also in areas of the brain not strictly adjacent to HIV-infected M/M.
人类免疫缺陷病毒（HIV）感染巨噬细胞（M/M）是导致艾滋病痴呆综合征患者神经元功能障碍和死亡的主要致病事件。即使神经元和星形胶质细胞未被感染，其活力在体内也会发生改变，因此可以想象，即使没有直接感染，HIV感染的M/M也可能影响这些细胞的活力。为了评估这一假设，我们研究了HIV感染的M/M对缺乏CD4受体表达的星形胶质细胞系的影响。暴露于HIV感染的M/M的上清液会引发星形胶质细胞的完全破坏和凋亡死亡。这种效应与HIV从感染的M/M传播无关，因为星形胶质细胞中的HIV-DNA和p24产生仍为阴性。星形胶质细胞的凋亡死亡主要由HIV感染的M/M的上清液中释放的Fas配体介导（通过添加针对CD95受体的中和抗体使这种现象完全逆转得以证明）。用重组（生物活性）Tat处理星形胶质细胞诱导的凋亡<10%，而gp120则完全无效。用齐多夫定（AZT）处理HIV感染的M/M可完全逆转其上清液对星形胶质细胞的促凋亡作用，从而表明M/M内有活性的病毒复制是诱导星形胶质细胞死亡所必需的。综上所述，数据表明在靶细胞没有有效感染的情况下，HIV感染的M/M可能会影响星形胶质细胞的内环境稳定。这种现象可能有助于解释在HIV感染患者中，即使在与HIV感染的M/M不严格相邻的脑区也发现的细胞损伤。
