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Journal of Virology, February 2007, p. 1492-1501, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01843-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cholesterol-Depleting Statin Drugs Protect Postmitotically Differentiated Human Neurons against Ethanol- and Human Immunodeficiency Virus Type 1-Induced Oxidative Stress In Vitro{triangledown}

Edward Acheampong,1 Zahida Parveen,1* Aschalew Mengistu,1 Noel Ngoubilly,1 Brian Wigdahl,2 Albert S. Lossinsky,3 Roger J. Pomerantz,4 and Muhammad Mukhtar2*

Dorrance H. Hamilton Laboratories, Division of Infectious Diseases, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Suite 329, Philadelphia, Pennsylvania 19107,1 Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102,2 Immunohistochemistry and Electron Microscopy Laboratories, Neural Engineering Program, Huntington Medical Research Institutes, Pasadena, California,3 Tibotec Inc., 1020 Stony Hill Road, Suite 300, Yardley, Pennsylvania 190674

Received 23 August 2006/ Accepted 7 November 2006

The majority of human immunodeficiency virus type 1 (HIV-1)-infected individuals are either alcoholics or prone to alcoholism. Upon ingestion, alcohol is easily distributed into the various compartments of the body, particularly the brain, by crossing through the blood-brain barrier. Both HIV-1 and alcohol induce oxidative stress, which is considered a precursor for cytotoxic responses. Several reports have suggested that statins exert antioxidant as well as anti-inflammatory pleiotropic effects, besides their inherent cholesterol-depleting potentials. In our studies, postmitotically differentiated neurons were cocultured with HIV-1-infected monocytes, T cells, or their cellular supernatants in the presence of physiological concentrations of alcohol for 72 h. Parallel cultures were pretreated with statins (atorvastatin and simvastatin) with the appropriate controls, i.e., postmitotically differentiated neurons cocultured with uninfected cells and similar cultures treated with alcohol. The oxidative stress responses in the presence/absence of alcohol in these cultures were determined by the production of the well-characterized oxidative stress markers, 8-isoprostane-F2-{alpha}, total nitrates as an indicator for various isoforms of nitric oxide synthase activity, and heat shock protein 70 (Hsp70). An in vitro culture of postmitotically differentiated neurons with HIV-1-infected monocytes or T cells as well as supernatants from these cells enhanced the release of 8-isoprostane-F2-{alpha} in the conditioned medium six- to sevenfold (monocytes) and four- to fivefold (T cells). It was also observed that coculturing of HIV-1-infected primary monocytes over a time period of 72 h significantly elevated the release of Hsp70 compared with that of uninfected controls. Cellular supernatants of HIV-1-infected monocytes or T cells slightly increased Hsp70 levels compared to neurons cultured with uninfected monocytes or T-cell supernatants (controls). Ethanol (EtOH) presence further elevated Hsp70 in both infected and uninfected cultures. The amount of total nitrates was significantly elevated in the coculture system when both infected cells and EtOH were present. Surprisingly, pretreatment of postmitotic neurons with clinically available inhibitors of HMG-coenzyme A reductase (statins) inhibited HIV-1-induced release of stress/toxicity-associated parameters, i.e., Hsp70, isoprostanes, and total nitrates from HIV-1-infected cells. The results of this study provide new insights into HIV-1 neuropathogenesis aimed at the development of future HIV-1 therapeutics to eradicate viral reservoirs from the brain.

* Corresponding author. Mailing address for Muhammad Mukhtar: Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Room 18107, Philadelphia, PA 19107. Phone: (215) 762-3719. Fax: (215) 762-1955. E-mail: muhammad.mukhtar{at}drexelmed.edu. Mailing address for Zahida Parveen: Dorrance H. Hamilton Laboratories, Division of Infectious Diseases, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Suite 329, Philadelphia, PA 19107. Phone: (215) 503-9097. Fax: (215) 923-1956. E-mail: zahida.parveen{at}jefferson.edu.

{triangledown} Published ahead of print on 15 November 2006.

Journal of Virology, February 2007, p. 1492-1501, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01843-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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