Cytomegalovirus (CMV) infections affect several thousand persons each year in the United States, and CMV-induced ocular disease results in considerable ophthalmologic morbidity. The widespread use of bone marrow transplantation and the recent epidemic of the acquired immune deficiency syndrome (AIDS) have dramatically increased the numbers of patients who are at risk for ocular disease caused by CMV. Although the clinical manifestations of CMV ocular disease, including retinitis, have been well-described, several critical questions regarding the pathogenesis of CMV retinitis in immunosuppressed patients have not been answered. In this proposal we will extend our previous observations regarding the pathogenesis of experimental CMV infection of ocular structures. The objective of this research proposal is to test the hypothesis that CMV develops latent infection of ocular structures and that immunosuppression modulates the ophthalmologic, virologic, and histopathologic expression of CMV in ocular tissues. We intend to use murine cytomegalovirus (MCMV) infection of mice and techniques of slitlamp microscopy, histology, virology, and molecular virology to address the following specific aims: 1) to assess the role of animal age and route of virus inoculation in determining the development of ocular MCMV infections, 2) to study the anatomic and cellular localization of MCMV in ocular tissues during acute, persistent, and latent MCMV infections, and 3) to study the role of immunosuppression in the production of histopathologic abnormalities during MCMV infection and in the reactivation of latent MCMV within ocular structures.
These specific aims will be accomplished by comparing the ophthalmologic, histopathologic, and virologic effects of MCMV infection in fetal, newborn, and weanling animals and by comparing the histologic findings and frequency of infection in mice receiving MCMV via different routes of virus inoculation. Subsequent studies will focus on the anatomic and cellular sites of MCMV replication and latency using detection of MCMV antigens by monoclonal antibodies and detection of MCMV genomic material using in situ DNA hybridization methods. The role of immunosuppression in the production of histologic abnormalities and reactivation of latent MCMV infection will be investigated by treating MCMV-infected mice with cyclophosphamide or hydrocortisone and antilymphocyte serum.
