Gene expression profiles of HIV-1-infected glia and brain: toward better understanding of the role of astrocytes in HIV-1-associated neurocognitive disorders

Abstract

Astrocytes are the major cellular component of the central nervous system (CNS), and they play multiple roles in brain development, normal brain function, and CNS responses to pathogens and injury. The functional versatility of astrocytes is linked to their ability to respond to a wide array of biological stimuli through finely orchestrated changes in cellular gene expression. Dysregulation of gene expression programs, generally by chronic exposure to pathogenic stimuli, may lead to dysfunction of astrocytes and contribute to neuropathogenesis. Here, we review studies that employ functional genomics to characterize the effects of HIV-1 and viral pathogenic proteins on cellular gene expression in astrocytes in vitro. We also present the first microarray analysis of primary mouse astrocytes exposed to HIV-1 in culture. In spite of different experimental conditions and microarray platforms used, comparison of the astrocyte array data sets reveals several common gene-regulatory changes that may underlie responses of these cells to HIV-1 and its proteins. We also compared the transcriptional profiles of astrocytes with those obtained in analyses of brain tissues of patients with HIV-1 dementia and macaques infected with simian immunodeficiency virus (SIV). Notably, many of the gene characteristics of responses to HIV-1 in cultured astrocytes were also altered in HIV-1 or SIV-infected brains. Functional genomics, in conjunction with other approaches, may help clarify the role of astrocytes in HIV-1 neuropathogenesis.

Fig. 1

Heatmap representing the signal values of chemokines and cytokines up-regulated in mouse astrocytes exposed to HIV-1. Red color represents up-regulation, and green color represents down-regulation. Uninfected controls are represented by C1, C2, and C3 and HIV-1-exposed mouse astrocytes by HIV1-1, HIV1-2, and HIV1-3. The selected chemokines and cytokines in the figure were significant with a t test p value of <0.05 and a fold change >2. The figure was generated using the values obtained from the ArrayAssist 5.5.1. software (Stratagene). Briefly, the RMA data values were calculated and transformed by variance stabilization, logarithmic scale, and baseline transformation. The final values were represented in a heatmap using Genesis software (http://genome.tugraz.at/)