The role of viral-induced apoptosis in the pathogenesis of human cytomegalovirus retinitis

• Main Authors: Shih-Hwa Chiou, 邱士華
• Other Authors: Wu-Tse Liu
• Format: Others
• Language: en_US
• Published: 2001
• Online Access: http://ndltd.ncl.edu.tw/handle/56360720775770692752

博士 === 國立陽明大學 === 臨床醫學研究所 === 90 === Human cytomegalovirus (HCMV), a member of the beta subfamily of herpes viruses, contains a double-stranded DNA genome of 229,354 base pairs with a potential to encode more than 200 proteins. HCMV infection usually develops asymptomatic lifelong infection in healthy individuals, but can cause severe clinical complications such as HCMV retinitis when reactivated in immunocompromised patients. Although the detailed mechanisms of HCMV latency and reactivation are not yet well understood, accumulating evidences suggest that the virus can use a panel of viral proteins to escape from cellular immune control and thus, successfully survive and replicate in host cells. Cellular immune reactions and the associated inflammatory responses can be harmful to nearby tissues. Since minor inflammation can result in impaired vision or even blindness, the eye is naturally designed as an immune privileged site where infections usually do not lead to destructive immune reactions. The underlying mechanism has been hypothesized to involve Fas ligand (FasL)-mediated programmed cell death (also called apoptosis) of Fas (CD95)-expressing T cells when attracted to the infection sites. In this case, activated T cells are eliminated through ligation of Fas by FasL and no serious immune reactions are induced. Thus, the damage to the eye is minimized. However, HCMV infection of human eyes is shown to cause large-scaled cell death and tremendous visual dysfunction. Whether HCMV takes the advantage of the FasL-dependent immune evasion to exert its destructive effects remains an important issue. Here we report that viral immediate early gene 2 (IE2), but not IE1, upregulates the Fas ligand (FasL) expression in HCMV-infected human retinal pigment epithelium (HRPE) cells. Increased secretion of FasL from virally infected cells into cultured medium was observed upon HCMV infection. The capability of such cell-free medium to induce apoptosis of Fas (CD95)-expressing Jurkat cells further implies that Fas-FasL interaction might mediate cell death in the lesion of HCMV retinitis. To support this idea, we observed augmented soluble FasL (sFasL) levels in vitreous from AIDS patients with HCMV retinitis as compared to that from AIDS patients without HCMV infection. In addition, by in situ hybridization and immunohistochemistry, we detected enhanced signals of FasL, the existence of viral IE antigens and apoptotic cells at the same sites in the lesion of HCMV-infected retina. These results strongly suggest that IE2 induction of FasL expression in human retina might be an important event that takes place in the early stage of infection and finally leads to visual loss in individuals affiliated with HCMV retinitis.