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 alpha 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.