Infection of human immunodeficiency virus and intracellular viral Tat protein exert a pro-survival effect in a human microglial cell line |
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Authors: | Chugh Pauline Fan Shongshan Planelles Vicente Maggirwar Sanjay B Dewhurst Stephen Kim Baek |
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Affiliation: | Department of Microbiology and Immunology, School of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14742, USA. |
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Abstract: | The interaction of human immunodeficiency virus type 1 (HIV-1) with CD4+ T lymphocytes is well studied and typically results in virally induced cytolysis. In contrast, relatively little is known concerning the interplay between HIV-1 and microglia. Recent findings suggest that, counter-intuitively, HIV-1 infection may extend the lifespan of microglia. We developed a novel cell line model system to confirm and mechanistically study this phenomenon. We found that transduction of a human microglial cell line with an HIV-1 vector results in a powerful cytoprotective effect following apoptotic challenge. This effect was reproduced by ectopic expression of a single virus-encoded protein, Tat. Subsequent studies showed that the pro-survival effects of intracellular Tat could be attributed to activation of the PI-3-kinase (PI3K)/Akt pathway in the microglial cell line. Furthermore, we found that expression of Tat led to decreased expression of PTEN, a negative regulator of the PI-3-K pathway. Consistent with this, decreased p53 activity and increased E2F activity were observed. Based on these findings, a model of possible regulatory circuits that intracellular Tat and HIV-1 infection engage during the cytoprotective event in microglia has been suggested. We propose that the expression of Tat may enable HIV-1 infected microglia to survive throughout the course of infection, leading to persistent HIV-1 production and infection in the central nervous system. |
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Keywords: | HIV-1, human immunodeficiency virus type 1 PTEN, phosphatase and tensin homolog CNS, central nervous system HCV, hepatitis type C virus HTLV-1, human T-cell leukemia virus type 1 PI-3-K, PI-3-kinase CHX, cycloheximide GFP, green fluorescent protein CMV, cytomegalovirus LPS, lipopolysaccharide SNP, sodium nitroprusside MOI, multiplicity of infection PBMC, peripheral blood mononuclear cells |
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