Human astrocytes were grown in culture and shown to secrete molecules which stimulated HIV-1 expression in a chronically infected promonocytic clone, U1.1.5. Interleukin-6, shown by others in the laboratory to synergize with TNF-alpha in stimulating HIV-1 expression in U1.1.5. cells, was detected in human and rat astrocyte-conditioned media. Transforming growth factor beta (TGF-beta) was detected in herpes zoster virus-infected human brain and in human and rat astrocytes exposed to HIV-1 in vitro. Interleukin-1 was found to stimulate TGF-beta expression in cultured rat astrocytes, microglia and oligodendrocytes. This stimulation was regulated post-transcriptionally in a time- and dose-dependent manner in primary rat astrocytes. These cells were also shown in vitro to secrete and bind endothelin-3 a potent vasoconstrictor. Exposure of rat granule neurons to HIV-1 resulted in their death. Brain isolate of HIV-1 BRVA was the most potent isolate tested in the destruction of neurons and neurites. Taken together, these results suggest that both direct and indirect mechanisms may operate in the neuropathogenesis of HIV-1 infection and that the indirect mechanism may involve astrocytic cytokines.
