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

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.

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“…Cultured adult DRG neurons have high metabolic requirements at a basal level (Russell et al, 1999, Russell et al, 2002, Vincent et al, 2004). Thus, the glucose concentrations used for culturing DRG neurons and for studying the effect of hyperglycemia on DRG neurons are much higher than blood glucose levels under physiological and hyperglycermic conditions in animals (Acheampong et al, 2009). Thus, the relevance of our in vitro findings to diabetic peripheral neuropathy warrants further investigation.…”

Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice

“…In the present study, glucose at 25 mmol/L was employed to optimally grow primary mouse Schwann cells, which has been used by many others to study Schwann cell biological functions (Honkanen et al, 2007, Paivalainen et al, 2008). However, in vivo a normal glucose level equals to approximately 5.5 mmol/L and a glucose concentration above 10 mmol/L is considered to be diabetic (Acheampong et al, 2009). We therefore employed immortalized Schwann cells, which permitted us to used glucose levels close to in vivo condition.…”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

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