Date Published:
2015 Oct

Publication Type:
Journal Article

Authors:

F. Zenón
Y. Cantres-Rosario
R. Adiga
M. Gonzalez
E. Rodriguez-Franco
D. Langford
L.M. Meléndez

Secondary:
J Neurovirol

Volume:
21

Pagination:
544-58

Issue:
5

PMID:
26092112

URL:
https://pubmed.ncbi.nlm.nih.gov/26092112

DOI:
10.1007/s13365-015-0358-7

Keywords:
AIDS Dementia Complex;Apoptosis;Blotting, Western;Cathepsin B;Cell Line;Cells, Cultured;Cystatin B;Cystatin C;Enzyme-Linked Immunosorbent Assay;External;Flow Cytometry;Fluorescent Antibody Technique;HIV-1;Humans;In Situ Nick-End Labeling;Microglia;Neurons

Abstract:
<p>HIV-1-infected mononuclear phagocytes release soluble factors that affect the homeostasis in tissue. HIV-1 can prompt metabolic encephalopathy with the addition of neuronal dysfunction and apoptosis. Recently, we reported that HIV-1 enhances the expression and secretion of bioactive cathepsin B in monocyte-derived macrophages, ultimately contributing to neuronal apoptosis. In this research, we asked if microglia respond to HIV infection similarly by modifying the expression, secretion, and neurotoxic potential of cathepsin B and determined the in vivo relevance of these findings. HIV-1ADA-infected human primary microglia and CHME-5 microglia cell line were assessed for expression and activity of cathepsin B, its inhibitors, cystatins B and C, and the neurotoxicity associated with these changes. Human primary neurons were exposed to supernatants from HIV-infected and uninfected microglia in the presence of cathepsin B inhibitors and apoptosis was assessed by TUNEL. Microglial expression of cathepsin B was validated in brain tissue from HIV encephalitis (HIVE) patients. HIV-infected microglia secreted significantly greater levels of cathepsin B, cystatin B, and cystatin C compared to uninfected cells. Increased apoptosis was observed in neurons exposed to supernatants from HIV-1 infected microglia at day 12 post-infection. The cathepsin B inhibitor CA-074 and cathepsin B antibody prevented neuronal apoptosis. Increased microglia-derived cathepsin B, cystatin B, and cystatin C and caspase-3+ neurons were detected in HIVE brains compared to controls. Our results suggest that HIV-1-induced cathepsin B production in microglia contributes to neuronal apoptosis and may be an important factor in neuronal death associated with HIVE.</p>