Susceptibility to murine cytomegalovirus retinitis during progression of MAIDS: correlation with intraocular levels of tumor necrosis factor-alpha and interferon-gamma

Abstract

Purpose: To correlate tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) synthesis with histopathologic disease and virus replication within murine cytomegalovirus (MCMV)-infected eyes during progression of murine acquired immunodeficiency syndrome (MAIDS).

Materials and methods: Groups of normal mice and mice with MAIDS of 2-weeks (MAIDS-2), 4-weeks (MAIDS-4), and 12-weeks (MAIDS-12) duration were infected uniocularly with MCMV by subretinal MCMV injection. MCMV-inoculated eyes from all mice were subjected to histopathologic analysis, quantitative plaque assay, or cytometric bead array analysis for quantification of TNF-alpha and IFN-gamma.

Results: Whereas MCMV-inoculated eyes of normal, MAIDS-2, and MAIDS-4 mice were resistant to MCMV retinitis, all MCMV-inoculated eyes of MAIDS-12 mice developed retinitis. Surprisingly, MCMV-inoculated eyes of MAIDS-4 mice without retinitis harbored high amounts of infectious virus at a level equivalent to that of MCMV-inoculated eyes of MAIDS-12 mice that developed retinitis. Intraocular TNF-alpha levels were consistently approximately 50% greater in MCMV-inoculated eyes of MAIDS-12 mice when compared with TNF-alpha levels of normal, MAIDS-2, and MAIDS-4 mice. In contrast, intraocular INF-gamma levels within MCMV-inoculated eyes progressively declined as animals became susceptible to retinitis.

Conclusions: An inverse relationship exists between TNF-alpha and INF-gamma production within MCMV-inoculated eyes during MAIDS evolution that is characterized by an increase in intraocular TNF-alpha levels and a concomitant decrease in intraocular INF-gamma levels. Susceptibility of MCMV-inoculated eyes to virus replication and development of necrotizing retinitis are independent events with susceptibility to MCMV replication preceding susceptibility to MCMV retinitis by several weeks. Time of Th1/Th2 shift in cytokine profile appears to be a crucial event in the pathogenesis of MAIDS-related MCMV retinitis.