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

Acheampong, Roschel Cassandra, Mukhtar Muhammad, Srinivasan Alagarsamy, Rafi Mohammad, Pomerantz, Parveen, Parveen Zahida

Description

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.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2009
• Nombre de lectures: 7
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

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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 effect s of hyperglycemic conditions and HIV-1 accessory protein Ne f on the CNS using both in vitro and in vivo models. Astrocytes, the most abundant glial cell type required for normal sy naptic 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 manne r. Delivery of purified recombinant HIV-1 Nef protein, or Nef expressed via HIV-1-based vectors in astrocyte s showed similar results. The expression of Nef protein delivered via HIV-1 ve ctors in combination with hyperglycemia further augmented the production of ROS, C3, activation of caspase-3, modulation of filamentous protein (F-protein), depolarization of th e 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 animal s. Interestingly, the delivery of HIV-1 Nef protein alone caused similar damage to CNS as augmented by hype rglycemia conditions. Taken together, the data suggests that HIV-1 infecte d individuals with hyperglycemia could potentially be at a higher risk of developing CNS related complications.

Published: 30 October 2009 Received: 4 May 2009 Virology Journal 2009, 6 :183 doi:10.1186/1743-422X-6-183  Accepted: 30 October 2009 This article is available from: h ttp://www.virologyj.com/content/6/1/183 © 2009 Acheampong et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the orig inal work is properly cited.

Virology Journal

Address: 1 The Dorrance H. Hamilton Laboratories, Division of Infe ctious Diseases and Environm ental Medicine, PA 19107, USA, 2 Bioscience Technologies - Biotechnology, Thomas Jefferson University, Philadelphia, PA 19107, USA, 3 Department of Biochemistry , Pir Mehr Ali Shah Arid Agriculture University Ra walpindi, 46300 Pakistan, 4 NanoBio Diagnostics, West Chester, PA 19382, USA, 5 Department of Neurology, Jefferson Medical College, Thomas Jefferson Univ ersity, Philadelphia, PA 19107, USA and 6 Tibotec Inc. 1020 Stony Hill Road , Suite 300, Yardley, PA 19067, USA Email: Edward A Acheampong - [e-mail]; Cassandra Roschel - [e-mail]; Muhammad Mukhtar - [e-mail]; Alagar samy Srinivasan - [e-mail]; Mohammad Rafi - [e-mail]; Roger J Pomerantz - [e-mail]; Zahida Parveen* - [e-mail] * Corresponding author

Research Open Access Combined effects of hyperglycemi c conditions and HIV-1 Nef: a potential model for induced HIV neuropathogenesis Edward A Acheampong 1 , Cassandra Roschel 2 , Muhammad Mukhtar 3 , Alagarsamy Srinivasan 4 , Mohammad Rafi 5 , Roger J Pomerantz 6 and Zahida Parveen* 1

Bio Med Central