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


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.
Dix
Richard D
RD
Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Dixrichardd@uams.edu
Cousins
Scott W
SW
D000818:Animals; D017726:Cytomegalovirus Retinitis / Q000209:etiology*; D018450:Disease Progression; D004198:Disease Susceptibility; D005123:Eye / Q000378:metabolism* / Q000821:virology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D018146:Muromegalovirus; D009336:Necrosis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*; D014779:Virus Replication
D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma