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 mechanism for the neurotoxicity of the HIV-1 envelope protein gp120.


METHODS
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) gp120SF2. Induction of cytokines was assayed by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR); neurotoxicity of rgp120SF2 and interleukin (IL)-6 on human brain cultures was examined by electron microscopy.


RESULTS
ELISA and RT-PCR studies revealed that rgp120SF2 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 TNF-alpha were upregulated in astrocytes and macrophage cultures on rgp120SF2 treatment. Ultrastructural studies demonstrated that IL-6 treatment for 72 h induced large cytoplasmic vacuoles in neural cells with morphology consistent with neurons; rgp120SF2 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 rgp120SF2 can upregulate at least two known neurotoxic cytokines, IL-6 and TNF-alpha, which may injure neural cells and contribute to the neuropathology observed in AIDS dementia patients.
Yeung
M C
MC
Moses Grossman Infectious Diseases Laboratory, Department of Pediatrics, San Francisco General Hospital, CA 94110, USA.
Pulliam
L
L
Lau
A S
AS
D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001483:Base Sequence; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D016923:Cell Death; D002478:Cells, Cultured; D003470:Culture Media; D018076:DNA, Complementary; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000648:ultrastructure; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D012313:RNA / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000633:toxicity
D003470:Culture Media; D018076:DNA, Complementary; D015699:HIV Envelope Protein gp120; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D012313:RNA