Estrogen receptor alpha inhibits the estrogen-mediated suppression of HIV transcription in astrocytes: implications for estrogen neuroprotection in HIV dementia.

Abstract

Many human immunodeficiency virus (HIV) proteins including Tat are produced by HIV-infected astrocytes and secreted into the brain resulting in extensive neuronal damage that contributes to the pathogenesis of HIV dementia. The neuroprotective hormone 17beta-estradiol (E2) is known to negatively regulate the HIV transcriptional promoter in human fetal astrocytes (SVGA cell line) in a Tat-dependent manner. In the present study we extended our investigation in HIV-infected SVGA cells and found a reduction in HIV p24 levels following E2 treatment in comparison to control. Although many E2-mediated events occur through estrogen receptor alpha (ERalpha), we found low levels of ERalpha mRNA and failed to detect ERalpha protein in SVGA cells. Paradoxically, when ERalpha was overexpressed the E2-mediated decrease in Tat transactivation of the promotor was prevented. To determine whether ERalpha expression is altered in the human brain following HIV infection, postmortum hippocampal tissue was obtained from cognitively normal HIV- and HIV+ patients, patients diagnosed with either mild cognitive/motor disorder (MCMD) or HIV-associated dementia (HAD). Immunohistochemistry and quantitative real-time PCR (qRT-PCR) for ERalpha and glial fibrillary acidic protein (GFAP) showed that ERalpha mRNA levels were not significantly different between groups, while GFAP increased in the hippocampus in the HIV+ compared to the HIV- group and was decreased in the MCMD and HAD subgroups compared to HIV+ controls. Notably the ratio of ERalpha-positive reactive astrocytes to total reactive astrocytes increased and significantly correlated with the severity of cognitive impairment following HIV infection. The data suggest that E2 would have the most dramatic effect in reducing HIV transcription early in the disease process when the subpopulation of astrocytes expressing ERalpha is low.