Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription through its intact core and cysteine-rich domains inhibits Wnt/β-catenin signaling in astrocytes: relevance to HIV neuropathogenesis

J Neurosci. 2012 Nov 14;32(46):16306-13. doi: 10.1523/JNEUROSCI.3145-12.2012.


Wnt/β-catenin is a neuroprotective pathway regulating cell fate commitment in the CNS and many vital functions of neurons and glia. Its dysregulation is linked to a number of neurodegenerative diseases. Wnt/β-catenin is also a repressor of HIV transcription in multiple cell types, including astrocytes, which are dysregulated in HIV-associated neurocognitive disorder. Given that HIV proteins can overcome host restriction factors and that perturbations of Wnt/β-catenin signaling can compromise astrocyte function, we evaluated the impact of HIV transactivator of transcription (Tat) on Wnt/β-catenin signaling in astrocytes. HIV clade B Tat, in primary progenitor-derived astrocytes and U87MG cells, inhibited Wnt/β-catenin signaling as demonstrated by its inhibition of active β-catenin, TOPflash reporter activity, and Axin-2 (a downstream target of Wnt/β-catenin signaling). Point mutations in either the core region (K41A) or the cysteine-rich region (C30G) of Tat abrogated its ability to inhibit β-catenin signaling. Clade C Tat, which lacks the dicysteine motif, did not alter β-catenin signaling, confirming that the dicysteine motif is critical for Tat inhibition of β-catenin signaling. Tat coprecipitated with TCF-4 (a transcription factor that partners with β-catenin), suggesting a physical interaction between these two proteins. Furthermore, knockdown of β-catenin or TCF-4 enhanced docking of Tat at the TAR region of the HIV long terminal repeat. These findings highlight a bidirectional interference between Tat and Wnt/β-catenin that negatively impacts their cognate target genes. The consequences of this interaction include alleviation of Wnt/β-catenin-mediated suppression of HIV and possible astrocyte dysregulation contributing to HIV neuropathogenesis.

Publication types

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

MeSH terms

  • AIDS Dementia Complex / pathology*
  • Astrocytes / physiology*
  • Blotting, Western
  • Cell Line
  • Cysteine / physiology
  • Flow Cytometry
  • Gene Products, tat / physiology
  • Genes, Reporter / genetics
  • Glutamic Acid / metabolism
  • HIV-1 / enzymology*
  • HIV-1 / genetics
  • Humans
  • Immunoprecipitation
  • Luciferases / metabolism
  • Plasmids / genetics
  • Point Mutation / physiology
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Transfection
  • Wnt Proteins / antagonists & inhibitors*
  • beta Catenin / antagonists & inhibitors*
  • rev Gene Products, Human Immunodeficiency Virus / chemistry
  • rev Gene Products, Human Immunodeficiency Virus / genetics
  • rev Gene Products, Human Immunodeficiency Virus / physiology*


  • Gene Products, tat
  • Wnt Proteins
  • beta Catenin
  • rev Gene Products, Human Immunodeficiency Virus
  • Glutamic Acid
  • Luciferases
  • Cysteine