THE HIV ENVELOPE PROTEIN GP120 IS TOXIC TO HUMAN BRAIN-CELL CULTURES THROUGH THE INDUCTION OF INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA

Objective: To investigate the induction of cytokines as a possible mec hanism for the neurotoxicity of the HIV-1 envelope protein gp120. Desi gn: The gp120 protein was tested directly on primary human brain cultu res to examine its ability to induce cytokines and its neurotoxicity o n human neural cells because gp120 is known to be toxic to rodent gang lion cultures, and neural cells such as astrocytes and microglia produ ce cytokines when stimulated. Methods: Primary cultures of human brain cell aggregates, astrocytes and macrophages were exposed to HIV-1 rec ombinant (r) gp120(SF2). Induction of cytokines was assayed by enzyme- linked immunosorbent assay (ELISA) and reverse transcriptase polymeras e chain reaction (RT-PCR); neurotoxicity of rgp120(SF2) and interleuki n (IL)-6 on human brain cultures was examined by electron microscopy. Results: ELISA and RT-PCR studies revealed that rgp120(SF2) induced IL -6 and tumor necrosis factor (TNF)-alpha in brain cultures; IL-6 could also be induced by TNF-alpha added to brain cultures. Both IL-6 and T NF-alpha were upregulated in astrocytes and macrophage cultures on rgp 120(SF2) treatment. Ultrastructural studies demonstrated that IL-6 tre atment for 72h induced large cytoplasmic vacuoles in neural cells with morphology consistent with neurons; rgp120(SF2) treatment for 7 days resulted in chromatin condensation along the inner margins of nuclear envelopes of neural cells. Conclusions: Our results demonstrated that HIV-1 rgp120(SF2) can upregulate at least two known neurotoxic cytokin es, IL-6 and TNF-alpha, which may injure neural cells and contribute t o the neuropathology observed in AIDS dementia patients.