Abstract
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-1ADA, 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.
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Acknowledgements
This research was supported in part by grants from the National Institutes of Health: R25-GM061838 (LR, KC), R01MH083516 (LMM) U54MD007600 (LMM), R25-GM082406, SC1GM11369–01 (LMM), and University of Puerto Rico School of Medicine and Biomedical Sciences Deanships. We thank the Puerto Rico Clinical and Translational Research Consortium (PRCTRC) grant U54MD007587 from National Institute on Minority Health and Health Disparities (NIMHD) and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health for the clinical support in obtaining samples from HIV-seronegative donors and for their partial support in obtaining the Nikon Eclipse E400, with a camera SPOT Insight QE and Fluorescence X-Cite Series 120 used in fluorescence assays.
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Rosario-Rodríguez, L., Colón, K., Borges-Vélez, G. et al. Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages. J Neuroimmune Pharmacol 13, 345–354 (2018). https://doi.org/10.1007/s11481-018-9794-5
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DOI: https://doi.org/10.1007/s11481-018-9794-5