Persistent “hijacking” of brain proteasomes in HIV-associated dementia

Human immunodeficiency virus-1 (HIV) infection of the central nervous system results in a syndrome of neuropsychological impairment, motor deficits, and behavioral changes diagnosed as HIV-associated dementia. Findings of increased ubiquitin-stained deposits and high molecular weight ubiquitin-protein conjugates in brains of HIV-positive subjects suggest impaired protein turnover by the ubiquitin-proteasome system analogous to neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. HIV infection of the brain and the consequent inflammatory response was hypothesized to alter the ubiquitin-proteasome system, leading to altered brain protein turnover and neuronal function. Investigations into the ubiquitin-proteasome system in HIV-infected brains were performed using the resources of the Texas NeuroAIDS Research Center and the National NeuroAIDS Tissue Consortium, including clinical data and frontal cortex brain tissue from 153 autopsy cases. Assessment of frontal cortex proteasome proteolytic activity revealed an abnormal catalytic profile that was more severe in those with HIV-associated neuropsychological impairment or HIV encephalitis. Proteasome subunit composition analysis by immunoblotting showed increases in immunoproteasome subunits LMP7 and PA28 alpha and decreases in constitutive proteasome regulatory subunit Rpn2 in the frontal cortex of HIV-positive subjects that correlated with the abnormal proteasome proteinase profile and were associated with neuropsychological impairment and HIV encephalitis. Immunoproteasome increases correlated with lower performance on neurocognitive tests specific for frontal lobe functioning domains, providing indications of regional specificity. Immunoproteasome increases also correlated with increases in frontal cortex tissue HIV loads. Immunoproteasomes were localized by immunofluorescence to the perikarya and distal processes of neurons, as well as to oligodendrocytes, astrocytes, and microglia. The potential consequence of immunoproteasomes in neurons was investigated with the analysis of synaptic proteins. Decreases in synaptophysin correlated with immunoproteasome increases, indicating the potential for synaptic protein alterations associated with immunoproteasomes. Analysis of isolated nerve endings, or synaptosomes, revealed immunoproteasome increases in synapses of HIV-positive subjects that correlated with increases in 14-3-3 zeta and decreases in synapsin 1. These findings suggest “hijacking” of constitutive proteasomes by immunoproteasomes with the persistent inflammatory response in HIV-infected brains. Ubiquitin-mediated protein turnover by constitutive proteasomes is consequently impaired, resulting in the dysregulation of neuronal and synaptic protein composition that leads to neuronal dysfunction.