IN-VITRO EVIDENCE FOR A DUAL ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA IN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENCEPHALOPATHY

Microglial cell activation, myelin alteration, and abundant tumor necr osis factor (TNF)-alpha message have been observed in the brains of so me human immunodeficiency virus type 1 (HIV-1)-infected and demented p atients. We therefore used cultures of purified human microglia and ol igodendrocytes derived from adult human brain to examine the role of T NF-alpha in HIV-1 encephalopathy. Human microglia synthesize TNF-alpha message and protein in vitro. When these cells were infected with HIV -1 JrFL and maintained in the presence of TNF-alpha antibodies, solubl e TNF-alpha receptors, or the THF-alpha inhibitor pentoxifylline, vira l replication was delayed or strongly inhibited. Both human microglia and oligodendrocytes express the two TNF receptors, TNF-R1, which has been implicated in cytotoxicity, and TNF-R2. While TNF-alpha may enhan ce HIV-1 replication in an autocrine manner, it is not toxic for micro glia. In contrast, recombinant human TNF-alpha causes oligodendrocyte death in a dose-dependent manner. In situ detection of DNA fragmentati on in some cells indicated that oligodendrocyte death may occur by apo ptosis. Addition of live microglia or medium conditioned by these cell s also resulted in 30 to 40% oligodendrocyte death, which was largely prevented by TNF-alpha inhibitors. We propose that TNF-alpha plays a d ual role in HIV-1 encephalopathy, enhancing viral replication by activ ated microglia and damaging oligodendrocytes. Thus, TNF-alpha inhibito rs may alleviate some of the neurological manifestations of acquired i mmunodeficiency syndrome.