Up-regulation of Fas ligand expression by human cytomegalovirus immediate-early gene product 2: A novel mechanism in cytomegalovirus-induced apoptosis in human retina

Human CMV (HCMV) is an important pathogen that causes widespread diseases i n immunocompromised individuals. Among the opportunistic HCMV infections, H CMV retinitis is most common in transplant recipients and AIDS patients. It often leads to blindness if left untreated. The question as to how HCMV in fection causes retinal pathogenesis remains unresolved. Here, we report tha t viral immediate-early gene product 2 (IE2), but not IE1, up-regulates the Fas ligand (FasL) expression in HCMV-infected human retinal pigment epithe lium cells. Increased secretion of FasL from virally infected cells into cu ltured medium was observed upon HCMV infection. The capability of such cell -free medium to induce apoptosis of Fas (CD95)-expressing Jurkat cells furt her implies that Fas-FasL interaction might mediate cell death in the lesio n of HCMV retinitis. To support this idea, we observed augmented soluble Fa sL levels in vitreous from AIDS patients with HCMV retinitis as compared wi th that from AIDS patients without HCMV infection. In addition, by in situ hybridization and immunohistochemistry, we detected enhanced signals of Fas L, the existence of viral IE Ags and apoptotic cells at the same sites in t he lesion of HCMV-infected retina. These results strongly suggest that IE2 induction of FasL expression in human retina might be an important event th at takes place in the early stage of infection and finally leads to visual loss in individuals affiliated with HCMV retinitis.