The HIV envelope protein gp120 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor-α

Abstract

Objective: To investigate the induction of cytokines as a possible mechanism for the neurotoxicity of the HIV-1 envelope protein gp120. Design: The gp120 protein was tested directly on primary human brain cultures to examine its ability to induce cytokines and its neurotoxicity on human neural cells because gp120 is known to be toxic to rodent ganglion cultures, and neural cells such as astrocytes and microglia produce cytokines when stimulated. Methods: Primary cultures of human brain cell aggregates, astrocytes and macrophages were exposed to HIV-1 recombinant(r) gp120(SF2) Induction of cytokines was assayed by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR); neurotoxicity of rgp120(SF2) and interleukin (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)-α in brain cultures; IL-6 could also be induced by TNF-α added to brain cultures. Both IL-6 and TNF-α were upregulated in astrocytes and macrophage cultures on rgp120(SF2) treatment. Ultrastructural studies demonstrated that IL-6 treatment 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 cytokines, IL-6 and TNF-α, which may injure neural cells and contribute to the neuropathology observed in AIDS dementia patients.