In vitro evidence for a dual role of tumor necrosis factor‐α in human immunodeficiency virus type 1 encephalopathy

Microglial cell activation, myelin alteration, and abundant tumor necrosis factor (TNF)‐α message have been observed in the brains of some human immunodeficiency virus type 1 (HIV ‐ 1)vinfected and demented patients. We therefore used cultures of purified human microglia and oligodendrocytes derived from adult human brain to examine the role of TNF‐α in HIV‐1 encephalopathy. Human microglia synthesize TNF‐α message and protein in vitro. When these cells were infected with HIV‐1 JrFL and maintained in the presence of TNF‐α antibodies, soluble TNF‐α receptors, or the TNF‐α inhibitor pentoxifylline, viral replication was delayed or strongly inhibited. Both human microglia and oligodendrocytes express the two TNF receptors, TNF‐Rl, which has been implicated in cytotoxicity, and TNF‐R2. While TNF‐α may enhance HIV‐1 replication in an autocrine manner, it is not toxic for microglia. In contrast, recombinant human TNF‐α causes oligodendrocyte death in a dose‐dependent manner. In situ detection of DNA fragmentation in some cells indicated that oligodendrocyte death may occur by apoptosis. Addition of live microglia or medium conditioned by these cells also resulted in 30 to 40% oligodendrocyte death, which was largely prevented by TNF‐α inhibitors. We propose that TNF‐α plays a dual role in HIV‐1 encephalopathy, enhancing viral replication by activated microglia and damaging oligodendrocytes. Thus, TNF‐α inhibitors may alleviate some ofthe neurological manifestations of acquired immunodeficiency syndrome.