title: HIV-infected microglia mediate cathepsin B-induced neurotoxicity.
abstract: 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.
authors.affiliation: Department of Microbiology and Medical Zoology, and Specialized Neuroscience Program in NeuroAIDS, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Frances
authors.initials: F
authors.lastname: Zenón
authors.affiliation: Department of Microbiology and Medical Zoology, and Specialized Neuroscience Program in NeuroAIDS, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Yisel
authors.initials: Y
authors.lastname: Cantres-Rosario
authors.affiliation: Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Adiga
authors.affiliation: Department of Biology, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico.
authors.forename: Mariangeline
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: Department of Microbiology and Medical Zoology, and Specialized Neuroscience Program in NeuroAIDS, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Eillen
authors.initials: E
authors.lastname: Rodriguez-Franco
authors.affiliation: Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: Langford
authors.affiliation: Department of Microbiology and Medical Zoology, and Specialized Neuroscience Program in NeuroAIDS, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico. loyda.melendez@upr.edu.|Department of Microbiology, School of Medicine, Medical Sciences Campus, San Juan, 00935, Puerto Rico. loyda.melendez@upr.edu.
authors.forename: Loyda M
authors.initials: LM
authors.lastname: Melendez
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002401:Cathepsin B / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D055313:Cystatin B / Q000378:metabolism; D055316:Cystatin C / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015497:HIV-1; D006801:Humans; D020287:In Situ Nick-End Labeling; D017628:Microglia / Q000378:metabolism / Q000821:virology*; D009474:Neurons / Q000473:pathology*
chemical_list: C525030:CST3 protein, human; C524994:CSTB protein, human; D055316:Cystatin C; D055313:Cystatin B; C533912:CTSB protein, human; D002401:Cathepsin B
keywords: Cathepsin B; Cystatins; HAND; Microglia; Post-mortem brain tissue