Journal
JOURNAL OF VIROLOGY
Volume 80, Issue 7, Pages 3273-3284Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.80.7.3273-3284.2006
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Funding
- NCI NIH HHS [P30 CA016672, CA16672] Funding Source: Medline
- NIEHS NIH HHS [ES07784, P30 ES007784] Funding Source: Medline
- NIMH NIH HHS [R01 MH071583, MH071583] Funding Source: Medline
- NINDS NIH HHS [NS043954, R44 NS043954] Funding Source: Medline
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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 Cl, results in accumulation of the ts1 gPr8(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 (CI-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.
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