Cathepsin B: A cysteine protease associated with HIV-neurocognitive disorders and aging

Abstract

August 20-22, 2012 C human immunodeficiency virus type one (HIV-1) infection leads to a spectrum of neurological and cognitive abnormalities, known collectively as HIV-associated neurocognitive disorders (HAND). HAND manifest in milder forms during despite effective combination antiretroviral therapy.The pathogenesis of HAND is thought to involve HIV-infected perivascular macrophages and microglia, whose activation leads to the release of pro-inflammatory cytokines and other soluble factors toxic to neurons. One factor that may be involved in macrophage-mediated HIV neurotoxicity is cathepsin B, a member of the cysteine protease family. We recently demonstrated that cathepsin B is upregulated in HIV-1 infected monocyte-derived macrophages (MDM), and secreted in a form that has increased neurotoxic activity in vitro and no longer interacted with its normal inhibitors, cystatin B and cystatin C. We recently observed increased expression of cathepsin B and cystatin B in monocytes of women with cognitive impairment, increased cathepsin B activity in plasma, and decreased cathepsin B activity in the CSF. A study of post-mortem brain tissue suggests that cathepsin B is also upregulated in brains from patients with HAND. We will present recent data related to the mechanisms whereby cathepsin B is dysregulated after HIV infection and how this dysregulation causes neuronal cell damage. This work was supported in part by NIH grants R01-MH08316-01, RCMI-NCRRG12RR03051, SNRP-NINDS-1-U54NS431.