Persistent hijacking of brain proteasomes in HIV-associated dementia

Am J Pathol. 2010 Feb;176(2):893-902. doi: 10.2353/ajpath.2010.090390. Epub 2009 Dec 24.

Abstract

Immunoproteasome induction sustains class 1 antigen presentation and immunological vigilance against HIV-1 in the brain. Investigation of HIV-1-associated alterations in brain protein turnover by the ubiquitin-proteasome system was performed by (1) determining proteasome subunit changes associated with persistent brain inflammation due to HIV-1; (2) determining whether these changes are related to HIV-1 neurocognitive disturbances, encephalitis, and viral loads; and (3) localizing proteasome subunits in brain cells and synapses. On the basis of neurocognitive performance, virological, and immunological measurements obtained within 6 months before death, 153 autopsy cases were selected. Semiquantitative immunoblot analysis performed in the dorsolateral prefrontal cortex revealed up to threefold induction of immunoproteasome subunits LMP7 and PA28alpha in HIV-1-infected subjects and was strongly related to diagnoses of neuropsychological impairment and HIV encephalitis. Low performance on neurocognitive tests specific for dorsolateral prefrontal cortex functioning domains was selectively correlated with immunoproteasome induction. Immunohistochemistry and laser confocal microscopy were then used to localize immunoproteasome subunits to glial and neuronal elements including perikarya, dystrophic axons, and synapses. In addition, HIV loads in brain tissue, cerebrospinal fluid, and blood plasma were robustly correlated to immunoproteasome levels. This persistent "hijacking" of the proteasome by HIV-1-mediated inflammatory response and immunoproteasome induction in the brain is hypothesized to impede turnover of folded proteins in brain cells. This would disrupt neuronal and synaptic protein dynamics, contributing to HIV-1 neurocognitive disturbances.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Dementia Complex / diagnosis
  • AIDS Dementia Complex / immunology*
  • AIDS Dementia Complex / metabolism*
  • AIDS Dementia Complex / pathology
  • Adult
  • Aging / metabolism
  • Aging / physiology
  • Antigen Presentation / physiology
  • Brain / metabolism*
  • Brain / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Diagnostic Techniques, Neurological
  • HIV-1 / immunology
  • HIV-1 / physiology
  • Humans
  • Multienzyme Complexes / metabolism
  • Muscle Proteins / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Endopeptidase Complex / physiology
  • Protein Subunits / metabolism
  • Proteins / immunology
  • Proteins / metabolism
  • Synapses / metabolism
  • Synapses / pathology

Substances

  • Multienzyme Complexes
  • Muscle Proteins
  • PSME1 protein, human
  • Protein Subunits
  • Proteins
  • LMP7 protein
  • Proteasome Endopeptidase Complex