Abstract
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.
Highlights
Antiretroviral therapy has been linked to insulin resistance and dyslipidemia in HIV infected individuals under treatment [1,2,3,4]
Our results indicate that the exposure of astrocytes to 10, 15, 20 and 25 mM glucose increased the expression of complement factor 3 (C3) (2.0, 4.0, 10 and 10.7 fold) in a dosedependent fashion respectively
Exposure of astrocytes to HIV-1 Nef alone enhanced the production of C3 to more than 4 fold, suggesting that HIV-1 Nef itself is capable of inducing immune response[20]
Summary
Antiretroviral therapy has been linked to insulin resistance and dyslipidemia in HIV infected individuals under treatment [1,2,3,4]. Since glucose is a major nutrient utilized by the brain[5], diabetes or HAART-associated hyperglycemic conditions may become a potential risk factor in the brain [6,7,8], and could lead to a series of devastating clinical conditions in the CNS of HIV-1 infected individuals[9]. Limited information is available regarding the combined effects of hyperglycemia and HIV-1 infection on the CNS. We selected astrocytes as target cells to evaluate the cumulative toxic effects of hyperglycemia and HIV-1 Nef protein. Limited information is available regarding the contributions of Nef alone and or in combination with hyperglycemic conditions to the pathogenesis of the CNS in the context of HIV-1 infection. The focus of this study was to evaluate the cytopathic effects of hyperglycemic conditions in the presence of HIV-1 Nef delivered either through HIV-1-
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