We have demonstrated that human astrocytes and two cell lines derived therefrom are capable of secreting cytokines known to be able to regulate human immunodeficiency virus (HIV) expression:interleukin-6 (IL-6), transforming growth factor-beta (TGF-Beta) and granulocyte macrophage-colony stimulating factor. The secretion of all three cytokines is stimulated in time- and dose-dependant manner by IL-1. IL-1 was found to stimulate TGF-Beta secretion by oligodendrocytes and microglia. These results suggest that the secretion of cytokines by glial cells may stimulate, at least in part, HIV expression in brain. Pre-existing IL-1 was found to be dramatically increased whereas TGF-Beta was induced in tissues from HIV-infected compared to seronegative individuals without neuropathology or brain disease. The HIV infected individuals whose brains were assayed displayed a broad range of neurological abnormalities characteristic of AIDS. All tissues from HIV-infected individuals displayed reactive astrocytosis but contained no perivascular infiltrates nor detectable HIV antigens (except in one case). Both cytokines were expressed by astrocytes and TGF-Beta was also expressed by microglia. IL-1 was also present in blood vessel endothelium whereas TGF-Beta was not. These results are consistant with those obtained in vitro and suggest that cytokines may be involved in the neuropathogenesis of HIV infection. However, the expression of these cytokines is not unique to HIV infection. The changes in the levels of IL-1 and TGF-Beta observed in AIDS brain were also observed in brains from patients with fever and several other disorders. These results suggest that these cytokines may be common mediators of the brains response to virus and other pathogenic insults rather than being specific to HIV infection. Nevertheless since cytokines such as TGF-Beta alter HIV expression in monocytic cells, they may at least in part determine the level of HIV expression in brain. We have demonstrated that murine brain cultures can become infected with a mixture of murine leukemia viruses known to cause immunodeficiency syndrome in mice. The data obtained in vivo and in vitro suggest that both microglia and astrocytes become infected. The data indicate that infected cells harbor a defective viral genome which has been previously demonstrated to be a critical component for disease induction. This animal model provides an opportunity for studying the molecular basis of retrovirus-mediated neuropathogenesis.
