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Hyperglycemic conditions associated with diabetes mellitus (DM) or with the use of antiretroviral therapy may increase the risk of central nervous system (CNS) disorders in HIV-1 infected patients. In support of this hypothesis, we investigated the combined effects of hyperglycemic conditions and HIV-1 accessory protein Nef on the CNS using both  in vitro  and  in vivo  models. Astrocytes, the most abundant glial cell type required for normal synaptic transmission and other functions were selected for our  in vitro  study. The results show that  in vitro  hyperglycemic conditions enhance the expression of proinflammatory cytokines including caspase-3, complement factor 3 (C3), and the production of total nitrate and 8-iso-PGF2 α as reactive oxygen species (ROS) in human astrocytes leading to cell death in a dose-dependent manner. Delivery of purified recombinant HIV-1 Nef protein, or Nef expressed via HIV-1-based vectors in astrocytes showed similar results. The expression of Nef protein delivered via HIV-1 vectors in combination with hyperglycemia further augmented the production of ROS, C3, activation of caspase-3, modulation of filamentous protein (F-protein), depolarization of the mitochondria, and loss of astrocytes. To further verify the effects of hyperglycemia and HIV-1 Nef protein on CNS individually or in combination,  in vivo  studies were performed in streptozotocin (STZ) induced diabetic mice, by injecting HIV-1 Nef expressing viral particles into the sub-cortical region of the brain. Our  in vivo  results were similar to  in vitro  findings indicating an enhanced production of caspases-3, ROS (lipid oxidation and total nitrate), and C3 in the brain tissues of these animals. Interestingly, the delivery of HIV-1 Nef protein alone caused similar damage to CNS as augmented by hyperglycemia conditions. Taken together, the data suggests that HIV-1 infected individuals with hyperglycemia could potentially be at a higher risk of developing CNS related complications.

Combined effects of hyperglycemic conditions and HIV-1 Nef: a potential model for induced HIV neuropathogenesis