AIDS-related human cytomegalovirus (HCMV)
retinitis continues to be a chronic ophthalmologic problem among human immunodeficiency virus type 1 (HIV-1)-infected patients who do not respond to
highly active antiretroviral therapy. Although HCMV
retinitis occurs during HIV-1-induced immunosuppression, the precise effector mechanism(s) that fails during the immunopathogenesis of
AIDS to allow onset and progression of HCMV
retinal disease remains unclear. We therefore performed a series of experiments to explore the relative roles of distinct pathways of lymphocyte-mediated cytotoxicity in either resistance or susceptibility to experimental murine cytomegalovirus (MCMV)
retinitis in mice. Whereas mutant C57BL/6 mice deficient in the Fas/FasL cytotoxic pathway (gld mice) were identical to normal C57BL/6 mice and exhibited absolute resistance to
retinal necrosis following subretinal MCMV inoculation, knockout C57BL/6 mice deficient in the
perforin cytotoxic pathway (PKO mice) were susceptible to MCMV
retinitis. Susceptibility of PKO mice to MCMV
retinitis correlated with increased ocular MCMV titers when compared with ocular MCMV titers of gld and normal mice. Since mice with retrovirus-induced immunodeficiency syndrome (
MAIDS) exhibited a frequency and severity of MCMV
retinitis that were equivalent to those observed in PKO mice, we hypothesized that susceptibility to MCMV
retinitis during
MAIDS correlates with a decrease in the
perforin cytotoxic pathway. To test this hypothesis, we developed a quantitative competitive reverse transcription-PCR assay to measure
mouse perforin mRNA levels in the splenic T lymphocytes and MCMV-inoculated eyes of normal mice or mice with
MAIDS.
Perforin mRNA levels in splenic T lymphocytes were significantly decreased during
MAIDS, by approximately 100-fold, from
perforin mRNA levels in normal mice. Moreover, MCMV-inoculated eyes destined to develop
retinitis during
MAIDS also showed a significant decrease in
perforin mRNA levels from the
perforin mRNA levels of MCMV-inoculated eyes of normal mice destined to be resistant to
retinitis. As expected,
perforin mRNA could not be detected in unmanipulated and uninfected eyes of normal mice. These results provide the first evidence that the
perforin cytotoxic pathway is more important than the Fas/FasL cytotoxic pathway in providing resistance to experimental MCMV
retinitis and that loss of the
perforin cytotoxic pathway predisposes to MCMV
retinitis.