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Richard D Dix, Christine Iris Alston; Murine Cytomegalovirus (MCMV)-Stimulated Ocular Suppressor of Cytokine Signaling (SOCS)1 and SOCS3 are Differentially Sensitive to Systemic Ganciclovir Treatment during MAIDS-Related MCMV Retinitis. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4496.
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© ARVO (1962-2015); The Authors (2016-present)
We use a clinically-relevant mouse model to study the pathophysiology of AIDS-related cytomegalovirus retinitis, a serious sight-threatening problem worldwide. We previously have shown (i) SOCS1 and SOCS3 are stimulated within MCMV-infected eyes of retinitis-susceptible mice during retrovirus-induced immunodeficiency (MAIDS), (ii) macrophages are among the intraocular SOCS1- and SOCS3-expressing cell types in this model, and (iii) MCMV infection of IC-21 mouse macrophages stimulates SOCS1 and SOCS3 expression. To determine the mechanism(s) whereby MCMV stimulates SOCS1 and SOCS3, we performed in vivo and in vitro experiments to test the hypothesis that MCMV-stimulated SOCS1 and/or SOCS3 expression is sensitive to the antiviral drug ganciclovir (GCV).
For in vivo studies, groups of mice (n=3-5) with MAIDS of 10 weeks’ duration (MAIDS-10) were injected subretinally with MCMV (left eyes) or media (right eyes), and received daily intraperitoneal injections of GCV (40 mg/kg) or vehicle (control). Whole eyes harvested at 3, 6, and 10 days after subretinal injection were assessed for SOCS1 and SOCS3 mRNA by real-time RT-PCR assay. For in vitro experiments, monolayers of IC-21 mouse macrophages were inoculated with MCMV (moi = 3) or media (control), and treated with 15 to 240 uM of GCV or vehicle (control). At 18 and 72 hrs postinfection (hpi), all monolayers were harvested and compared by real-time RT-PCR assay for SOCS1 and SOCS3 mRNA production.
Systemic GCV treatment of MAIDS-10 mice significantly decreased MCMV stimulation of ocular SOCS1, but not SOCS3, mRNA expression by day 6. In IC-21 cells at 72 hpi, MCMV infection without GCV resulted in stimulation of SOCS1 and SOCS3 mRNA, but GCV treatment reduced this stimulation in a dose-dependent manner.
Whereas MCMV stimulation of ocular SOCS1, but not SOCS3, in MAIDS-10 mice was sensitive to GCV in vivo, MCMV-stimulated SOCS3 showed greater GCV sensitivity than SOCS1 in IC-21 cells. These differences in GCV sensitivity suggest that mechanism(s) by which MCMV stimulates SOCS1 and SOCS3 during MAIDS-related MCMV retinitis may involve a number of retinal cell types beyond macrophages. Additional experiments with MAIDS-12 mice are underway to determine whether this persists at later times during MAIDS progression.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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