Dysregulation of macrophage-secreted cathepsin B contributes to HIV-1-linked neuronal apoptosis

PLoS One. 2012;7(5):e36571. doi: 10.1371/journal.pone.0036571. Epub 2012 May 31.


Chronic HIV infection leads to the development of cognitive impairments, designated as HIV-associated neurocognitive disorders (HAND). The secretion of soluble neurotoxic factors by HIV-infected macrophages plays a central role in the neuronal dysfunction and cell death associated with HAND. One potentially neurotoxic protein secreted by HIV-1 infected macrophages is cathepsin B. To explore the potential role of cathepsin B in neuronal cell death after HIV infection, we cultured HIV-1(ADA) infected human monocyte-derived macrophages (MDM) and assayed them for expression and activity of cathepsin B and its inhibitors, cystatins B and C. The neurotoxic activity of the secreted cathepsin B was determined by incubating cells from the neuronal cell line SK-N-SH with MDM conditioned media (MCM) from HIV-1 infected cultures. We found that HIV-1 infected MDM secreted significantly higher levels of cathepsin B than did uninfected cells. Moreover, the activity of secreted cathepsin B was significantly increased in HIV-infected MDM at the peak of viral production. Incubation of neuronal cells with supernatants from HIV-infected MDM resulted in a significant increase in the numbers of apoptotic neurons, and this increase was reversed by the addition of either the cathepsin B inhibitor CA-074 or a monoclonal antibody to cathepsin B. In situ proximity ligation assays indicated that the increased neurotoxic activity of the cathepsin B secreted by HIV-infected MDM resulted from decreased interactions between the enzyme and its inhibitors, cystatins B and C. Furthermore, preliminary in vivo studies of human post-mortem brain tissue suggested an upregulation of cathepsin B immunoreactivity in the hippocampus and basal ganglia in individuals with HAND. Our results demonstrate that HIV-1 infection upregulates cathepsin B in macrophages, increases cathepsin B activity, and reduces cystatin-cathepsin interactions, contributing to neuronal apoptosis. These findings provide new evidence for the role of cathepsin B in neuronal cell death induced by HIV-infected macrophages.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis*
  • Basal Ganglia / metabolism
  • Basal Ganglia / pathology
  • Basal Ganglia / physiopathology
  • Basal Ganglia / virology
  • Cathepsin B / antagonists & inhibitors
  • Cathepsin B / genetics
  • Cathepsin B / metabolism*
  • Cell Line, Tumor
  • Cognition
  • Cystatin B / genetics
  • Cystatin B / metabolism
  • Cystatin C / genetics
  • Cystatin C / metabolism
  • Female
  • Gene Expression Regulation, Enzymologic
  • HIV-1 / physiology*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Hippocampus / virology
  • Humans
  • Intracellular Space / metabolism
  • Intracellular Space / virology
  • Lysosomes / metabolism
  • Lysosomes / virology
  • Macrophages / metabolism*
  • Macrophages / virology
  • Monocytes / cytology
  • Neurons / cytology*
  • Neurons / virology*


  • Cystatin C
  • Cystatin B
  • Cathepsin B