Human immunodeficiency virus-1 uses the mannose-6-phosphate receptor to cross the blood-brain barrier

PLoS One. 2012;7(6):e39565. doi: 10.1371/journal.pone.0039565. Epub 2012 Jun 25.


HIV-1 circulates both as free virus and within immune cells, with the level of free virus being predictive of clinical course. Both forms of HIV-1 cross the blood-brain barrier (BBB) and much progress has been made in understanding the mechanisms by which infected immune cells cross the blood-brain barrier BBB. How HIV-1 as free virus crosses the BBB is less clear as brain endothelial cells are CD4 and galactosylceramide negative. Here, we found that HIV-1 can use the mannose-6 phosphate receptor (M6PR) to cross the BBB. Brain perfusion studies showed that HIV-1 crossed the BBB of all brain regions consistent with the uniform distribution of M6PR. Ultrastructural studies showed HIV-1 crossed by a transcytotic pathway consistent with transport by M6PR. An in vitro model of the BBB was used to show that transport of HIV-1 was inhibited by mannose, mannan, and mannose-6 phosphate and that enzymatic removal of high mannose oligosaccharide residues from HIV-1 reduced transport. Wheatgerm agglutinin and protamine sulfate, substances known to greatly increase transcytosis of HIV-1 across the BBB in vivo, were shown to be active in the in vitro model and to act through a mannose-dependent mechanism. Transport was also cAMP and calcium-dependent, the latter suggesting that the cation-dependent member of the M6PR family mediates HIV-1 transport across the BBB. We conclude that M6PR is an important receptor used by HIV-1 to cross the BBB.

Publication types

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

MeSH terms

  • Animals
  • Biological Transport
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / virology
  • Brain / metabolism*
  • Brain / virology
  • Calcium / metabolism
  • Cyclic AMP / metabolism
  • Endothelial Cells / metabolism
  • Endothelial Cells / virology
  • HIV-1 / metabolism*
  • Male
  • Mice
  • Receptor, IGF Type 2 / metabolism*
  • Signal Transduction / physiology
  • Transcytosis / physiology*
  • Wheat Germ Agglutinins / metabolism


  • Receptor, IGF Type 2
  • Wheat Germ Agglutinins
  • Cyclic AMP
  • Calcium