Cytokine Augmentation of HIV-1 LTR-Driven Gene Expression in Neural Cells

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Abstract
The induction of human immunodeficiency virus type 1 (HIV-1) gene expression by cytokines was investigated in cells of central nervous system origin. These were human neuroblastoma, glioblastoma, and astrocytoma cell lines, a murine oligodendroglioma and primary murine astrocyte cultures. The cytokines used were tumor necrosis factor alpha (TNFα), interleukin-lβ (IL-lβ), IL-6, and interferons alpha and gamma (IFNβ, γ). Transient transfection of cells with a chloramphenicol acetyltransferase (CAT) reporter gene under the control of the HIV-1 long terminal repeat (LTR) showed significant augmentation following treatment by particular cytokines. TNFα was found to augment HIV LTR-directed CAT activity in all cell types. IL-lβ also activated the HIV LTR reporter gene in glioblastoma, astrocytoma, and astrocyte cells. IL-6 enhanced HIV gene expression in one example only, the primary astrocyte cultures. The interferons generally suppressed expression from the LTR except IFNγ which produced a twofold rise in the murine glial cells and IFNα augmenting expression in one neuroblastoma cell line. No synergy was observed between pairs of activating cytokines tested. The HIV tat gene product was found to be functional in all cells, cotransfection of a tat expression vector transactivating expression from the LTR, with varying degrees of efficiency. In some cell lines the combination of an activating cytokine and tat resulted in an enhancement above that obtained by cotransfection of tat alone. In others, the level of CAT activity did not significantly change. Analysis of nuclear extracts from cytokine-treated cells further implicated the involvement of NFkB in the induction of HIV-1 gene expression. In the neuroblastoma cells exposed to TNFα, and astrocytoma cells to IL-lβ, NFkB-like binding activity was detected following cytokine-treatment in gel retardation assays. These results suggest that the latent, or low-level infection found in neural cells may be activated by certain cytokines in patients with HIV encephalopathy.