Altered microglial gene expression in HIV infection: insights into the complex role of microglia in neurodegenerative disease
Stephen D. Ginsberg1, 2, Melissa J. Alldred1, 2, Satya M. Gunnam3, Consuelo Schiroli3, Sang Han Lee1, 2, Susan Morgello4, and Tracy Fischer3
1Nathan Kline Institute, Orangeburg, NY; 2NYU Langone Medical Center, New York, NY; 3Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA; 4Departments of Neurology, Pathology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY
Neuroinflammation, rather than productive HIV in brain, is a common complication of HIV infection. We previously reported substantial accumulation of CD163+/CD16+ microglia in brain of patients with HIV encephalitis (HIVE), a neuropathological correlate of HIV-associated dementia. More recently, we found neurocognitively impaired HIV+ persons without encephalitis (HIV/noE) or productive HIV in brain also have CD163+ and CD16+ microglia. To further our understanding of microglial function in HIV, we investigated gene expression changes of select classes of microglial transcripts from archival brain tissue of patients with HIVE, HIV/noE, and seronegative (HIV-) controls. Microarray analyses were performed on ~2,500 laser capture microdissected CD163+, CD16+, or CD68+ microglia, using terminal continuation RNA amplification and a custom-designed array platform. These studies revealed several classes of microglial transcripts are altered in HIV infection, with and without encephalitis or detectable virus production in brain, including genes associated with cell stress, inflammation, apoptosis, and neurotrophic factors. The majority of transcripts impacted in HIVE showed intermediate changes in HIV/noE, suggesting a continuum of microglial impairment that may result from prolonged neuroinflammation. Our work provides important insights into the diverse roles microglia play in maintaining brain homeostasis and how impaired microglial function may contribute to neuronal injury and cognitive impairment in neurodegenerative disease. Additionally, this work shows the utility of profiling microglia to increase our understanding of microglial function, as well as impairments that may be amenable to targeted treatment modalities in diseases affecting the brain.