Increased CDK5 expression in HIV encephalitis contributes to neurodegeneration via tau phosphorylation and is reversed with Roscovitine

Am J Pathol. 2011 Apr;178(4):1646-61. doi: 10.1016/j.ajpath.2010.12.033.


Recent treatments with highly active antiretroviral therapy (HAART) regimens have been shown to improve general clinical status in patients with human immunodeficiency virus (HIV) infection; however, the prevalence of cognitive alterations and neurodegeneration has remained the same or has increased. These deficits are more pronounced in the subset of HIV patients with the inflammatory condition known as HIV encephalitis (HIVE). Activation of signaling pathways such as GSK3β and CDK5 has been implicated in the mechanisms of HIV neurotoxicity; however, the downstream mediators of these effects are unclear. The present study investigated the involvement of CDK5 and tau phosphorylation in the mechanisms of neurodegeneration in HIVE. In the frontal cortex of patients with HIVE, increased levels of CDK5 and p35 expression were associated with abnormal tau phosphorylation. Similarly, transgenic mice engineered to express the HIV protein gp120 exhibited increased brain levels of CDK5 and p35, alterations in tau phosphorylation, and dendritic degeneration. In contrast, genetic knockdown of CDK5 or treatment with the CDK5 inhibitor roscovitine improved behavioral performance in the water maze test and reduced neurodegeneration, abnormal tau phosphorylation, and astrogliosis in gp120 transgenic mice. These findings indicate that abnormal CDK5 activation contributes to the neurodegenerative process in HIVE via abnormal tau phosphorylation; thus, reducing CDK5 might ameliorate the cognitive impairments associated with HIVE.

MeSH terms

  • Adult
  • Animals
  • Brain / metabolism
  • Brain / virology
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Female
  • Frontal Lobe / metabolism
  • Gene Expression Regulation*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Human Immunodeficiency Virus Proteins / metabolism*
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Neurodegenerative Diseases / virology
  • Phosphotransferases / metabolism
  • Purines / pharmacology
  • Roscovitine
  • Signal Transduction
  • tau Proteins / chemistry
  • tau Proteins / metabolism*


  • Cdk5r1 protein, mouse
  • Human Immunodeficiency Virus Proteins
  • Purines
  • tau Proteins
  • Roscovitine
  • Phosphotransferases
  • Cyclin-Dependent Kinase 5
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3