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

Authors

Edward A Acheampong, The Dorrance H. Hamilton Laboratories, Division of Infectious Diseases and Environmental Medicine, PA 19107, USAFollow
Cassandra Roschel, Bioscience Technologies - Biotechnology, Thomas Jefferson University, Philadelphia, PA 19107, USAFollow
Muhammad Mukhtar, Department of Biochemistry, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, 46300 PakistanFollow
Alagarsamy Srinivasan, NanoBio Diagnostics, West Chester, PA 19382, USAFollow
Mohammad Rafi, Department of Neurology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107Follow
Roger J Pomerantz, Tibotec Inc. 1020 Stony Hill Road, Suite 300, Yardley, PA 19067, USA Email: Edward A Acheampong - eacheaFollow
Zahida Parveen, The Dorrance H. Hamilton Laboratories, Division of Infectious Diseases and Environmental Medicine, PA 19107, USAFollow

Document Type

Article

Publication Date

1-1-2009

Comments

This article has been peer reviewed and is published in Virology Journal Volume 6, 2009, Article number 183. The published version is available at DOI: 10.1186/1743-422X-6-183. Copyright © BioMed Central Ltd.

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 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.

Recommended Citation

Acheampong, Edward A; Roschel, Cassandra; Mukhtar, Muhammad; Srinivasan, Alagarsamy; Rafi, Mohammad; Pomerantz, Roger J; and Parveen, Zahida, "Combined effects of hyperglycemic conditions and HIV-1 Nef: a potential model for induced HIV neuropathogenesis." (2009). Department of Neurology Faculty Papers. Paper 33.
https://jdc.jefferson.edu/neurologyfp/33

PubMed ID

19878567