Date Published:
2015 Oct 23
Publication Type:
Journal Article
Authors:
Secondary:
AIDS
Volume:
29
Pagination:
2081-92
Issue:
16
PMID:
26208400
URL:
https://pubmed.ncbi.nlm.nih.gov/26208400
DOI:
10.1097/QAD.0000000000000823
Keywords:
Apoptosis;Cathepsin B;Cells, Cultured;Culture Media, Conditioned;External;Female;HIV Infections;HIV-1;Humans;Macrophages;Neurons
Abstract:
<p>OBJECTIVE: HIV-1 infection of macrophages increases cathepsin B secretion and induces neuronal apoptosis, but the molecular mechanism remains unclear.DESIGN: We identified macrophage-secreted cathepsin B protein interactions extracellularly and their contribution to neuronal death in vitro.METHODS: Cathepsin B was immunoprecipitated from monocyte-derived macrophage supernatants after 12 days postinfection. The cathepsin B interactome was identified by label-free tandem mass spectrometry and compared with uninfected supernatants. Proteins identified were validated by western blot. Neurons were exposed to macrophage-conditioned media in presence or absence of antibodies against cathepsin B and interacting proteins. Apoptosis was measured using TUNEL labeling. Immunohistochemistry of postmortem brain tissue samples from healthy, HIV-infected and Alzheimer's disease patients was performed to observe the ex-vivo expression of the proteins identified.RESULTS: Nine proteins co-immunoprecipitated differentially with cathepsin B between uninfected and HIV-infected macrophages. Serum amyloid P component (SAPC)-cathepsin B interaction increased in HIV-infected macrophage supernatants, while matrix metalloprotease 9 (MMP-9)-cathepsin B interaction decreased. Pre-treatment of HIV-infected macrophage-conditioned media with antibodies against cathepsin B and SAPC decreased neuronal apoptosis. The addition of MMP-9 antibodies was not neuro-protective SAPC was overexpressed in postmortem brain tissue from HIV-positive neurocognitive impaired patients compared with HIV positive with normal cognition and healthy controls, although MMP-9 expression was similar in all tissues.CONCLUSION: Inhibiting SAPC-cathepsin B interaction protects against HIV-induced neuronal death and may help to find alternative treatments for HIV-associated neurocognitive disorders.</p>