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Journal of Virology, April 2006, p. 3273-3284, Vol. 80, No. 7
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.7.3273-3284.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Astrocytes Survive Chronic Infection and Cytopathic Effects of the ts1 Mutant of the Retrovirus Moloney Murine Leukemia Virus by Upregulation of Antioxidant Defenses

Wenan Qiang,^* Xianghong Kuang, Jinrong Liu, Na Liu, Virginia L. Scofield, Amy J. Reid, Yuhong Jiang, Gheorghe Stoica,^¶ William S. Lynn, and Paul K. Y. Wong^*

Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, Texas 78957

Received 28 July 2005/ Accepted 10 January 2006

The ts1 mutant of Moloney murine leukemia virus (MoMuLV) induces a neurodegenerative disease in mice, in which glial cells are infected by the retrovirus but neurons are not. ts1 infection of primary astrocytes, or of the immortalized astrocytic cell line C1, results in accumulation of the ts1 gPr80^env envelope protein in the endoplasmic reticulum (ER), with ER and oxidative stress. Notably, only about half of the infected astrocytes die in these cultures, while the other half survive, continue to proliferate, and continue to produce virus. To determine how these astrocytes survive ts1 infection in culture, we established a chronically infected subline of the living cells remaining after the death of all acutely infected cells in an infected C1 cell culture (C1-ts1-S). We report here that C1-ts1-S cells proliferate more slowly, produce less virus, show reduced H₂O₂ levels, increase their uptake of cystine, and maintain higher levels of intracellular GSH and cysteine compared to acutely infected or uninfected C1 cells. C1-ts1-S cells also upregulate their thiol antioxidant defenses by activation of the transcription factor NF-E2-related factor 2 (Nrf2) and its target genes. Interestingly, despite maintenance of higher levels of intracellular reduced thiols, C1-ts1-S cells are more sensitive to cystine deprivation than uninfected C1 cells. We conclude that some ts1-infected astrocytes survive and adapt to virus-induced oxidative stress by successfully mobilizing their thiol redox defenses.

Present address: Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.

Present address: Department of Pharmacology, School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, People's Republic of China.

Present address: Drug Metabolism Department, Abbott Laboratories, Abbott Park, IL 60064.

^¶ Present address: Department of Pathobiology, Texas A&M University College of Veterinary Medicine, College Station, TX 77843.

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