Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages

• Published in: Journal of neuroimmune pharmacology 2018-09, Vol.13 (3), p.345-354
• Main Authors: Rosario, Lester, Colón, Krystal, Borges, Gabriel, Negrón, Karla, Meléndez, Loyda M.
• Format: Article
• Language: English
• Subjects: AIDS Dementia Complex - pathology; Antioxidants - therapeutic use; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; Cathepsin B - metabolism; Cell Biology; Dimethyl Fumarate - therapeutic use; HIV; HIV Core Protein p24 - metabolism; HIV Infections - pathology; HIV Infections - prevention & control; HIV-1 - drug effects; Human immunodeficiency virus; Humans; Immunology; In Situ Nick-End Labeling; Macrophages - drug effects; Macrophages - metabolism; Neurosciences; Neurotoxicity; Original Article; Oxidative stress; Oxidative Stress - drug effects; Pharmacology/Toxicology; Reactive Nitrogen Species - metabolism; Reactive Oxygen Species - metabolism; Virology; Virus Replication - drug effects
• ISSN: 1557-1890; 1557-1904
• DOI: 10.1007/s11481-018-9794-5

HIV-associated neurocognitive disorders (HAND) are prevalent despite combined antiretroviral therapy, affecting nearly half of HIV-infected patients worldwide. During HIV infection of macrophages secretion of the lysosomal protein, cathepsin B, is increased. Secreted cathepsin B has been shown to induce neurotoxicity. Oxidative stress is increased in HIV-infected patients, while antioxidants are decreased in monocytes from patients with HIV-associated dementia (HAD). Dimethyl fumarate (DMF), an antioxidant, has been reported to decrease HIV replication and neurotoxicity mediated by HIV-infected macrophages. Thus, we hypothesized that DMF will decrease cathepsin B release from HIV-infected macrophages by preventing oxidative stress and enhancing lysosomal function. Monocyte-derived macrophages (MDM) were isolated from healthy donors, inoculated with HIV-1 ADA, and treated with DMF following virus removal. After 12 days post-infection, HIV-1 p24 and total cathepsin B levels were measured from HIV-infected MDM supernatants using ELISA; intracellular reactive oxygen and nitrogen species (ROS/RNS) were measured from MDM lysates, and functional lysosomes were assessed using a pH-dependent lysosomal dye. Neurons were incubated with serum-free conditioned media from DMF-treated MDM and neurotoxicity was determined using TUNEL assay. Results indicate that DMF reduced HIV-1 replication and cathepsin B secretion from HIV-infected macrophages in a dose-dependent manner. Also, DMF decreased intracellular ROS/RNS levels, and prevented HIV-induced lysosomal dysfunction and neuronal apoptosis. In conclusion, the improvement in lysosomal function with DMF treatment may represent the possible mechanism to reduce HIV-1 replication and cathepsin B secretion. DMF represents a potential therapeutic strategy against HAND.