Mechanisms that explain how HIV-1 causes damage in the pediatric brain have focused on alternative explanations; either HIV-1 can induce toxins from infected macrophages and/or cause a low level infection in select populations of glial cells. We have established a useful model of HIV-1 infection in human fetal brain cell cultures to address this question. Through either infection with virions or transfection with proviral DNA, human fetal astrocytes, which do not express the CD4 receptor for HIV-1, quickly develop a non-cytopathic but productive infection which gradually diminishes to a persistent infection. Persistence of the viral genome is maintained in an integrated state in the host chromosome without expression at the RNA or protein levels. However, HIV-1 can be activated by factors provided by CD4 + human lymphocytes. Cytokines TNF-alpha and II-1 beta are also able to activate the latent HIV-1 genome following transfection, to again progress into a productive but limited infection. Other cytokines known to induce HIV-1 from human monocyte cells such as GM-CSF, II-6,II-2, and interferon do not activate HIV-1 from astrocyte. Further evidence of the specificity of these cytokines comes from experiments using an HIV-1 LTR CAT vector transfected into astroctyes. CAT activity is highest in cells treated with TNF-alpha and II-1 beta even in the absence of the viral transactivator, tat protein. Within 24 hrs of cytokine addition to persistently infected astrocytes, HIV-1 mRNAs for nef, tat, and rev proteins can be identified. The nef transcript appears to be the most abundant HIV-1 transcript. Examination of brain tissues from 12 pediatric AIDS cases also revealed astrocytes, GFAP staining, with positive hybridization to HIV-1 radiolabeled probes in 4 cases. In several of these sections, there was no evidence for HIV-1 antigens, p24 and gp 41. These results suggest that astrocytes may harbor an unexpressed HIV-1 proviral DNA that can be activated in the brain through cytokines. TNF-alpha and II-1 beta are reported to be present in AIDS brain tissue in high concentrations. Further study of the molecular mechanism of transcriptional control of HIV-1 and its clinical correlates in pediatric AIDS encephalopathy are currently in progress.
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