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

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 represent the possible mechanism to reduce hiv-1 replication and cathepsin b secretion. dmf represents a potential therapeutic strategy against hand.