HIV-1 INFECTION IN FETAL BRAIN CELL CULTURES AND PEDIATRIC AIDS BRAIN TISSUE

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Possible causes of HIV-1- induced neurotoxicity include infection of select populations of glial cells. We have established a useful model of HIV-1 infection in human fetal brain cell cultures to study the mechanisms by which this may occur. Through either infection with virions or transfection with proviral DNA, human fetal astrocytes quickly develop a non-cytopathic but productive infection which gradually diminishes to a persistent infection without viral expression at the RNA or protein levels. However, HIV-1 expression can be reactivated by the cytokines TNF-alpha and IL-1 beta as well as by phorbol myristic acid (PMA), a potent activator of protein kinase C. PKC inhibitors such as H-7, an isoquinolone, can block reactivation by TNF-alpha and PMA, an effect which in the case of PMA is likely due to a reduction in the transcriptional activator NF kappa-B. Intracellular pathways involved in HIV~1 reactivation appear to be cell-type dependent as other factors known to induce HIV-1 from human monocyte cells such as GM-CSF, IL-6, IL-2 and interferon do not activate HIV-1 from astrocytes. Extraction of mRNA following stimulation with TNF-alpha or IL-1 beta demonstrates the presence of mRNA for nef, tat and rev proteins, of which nef is the most abundant and longest lasting. We have evidence that infection of glial cells is important in vivo in that tissue from 4 of 12 pediatric AIDS brains has revealed glial fibrillary acidic protein (GFAP) positive astrocytes with positive hybridization to HIV-1 radiolabeled probes. In several of these sections, there was no evidence for the HIV-1 antigens p24 and gp41. These results suggest that astrocytes may harbor an undetectable HIV-1 proviral DNA that can be activated in the brain through cytokines. TNF-alpha and IL-1 beta are reported to be present in AIDS brain tissue in high concentrations. Other work has shown that these cytokines are produced by astrocytes in response to HIV infection. Further study of the molecular and biochemical aspects of HIV~1 infection of astrocytes and its clinical correlates in pediatric AIDS encephalopathy are currently in progress.