Adenoviruses (Ads) are ubiquitous in nature and cause many medical problems including ocular disease around the world. In the United States, Ads are the most common cause of acute viral infections of the eye for which there are no effective antiviral drugs. Clinically, they cause epidemic keratoconjunctivitis (EKC), pharyngeal conjunctival fever, and non-specific follicular conjunctivitis. Ads also cause a significant portion of the complications seen in AIDS patients and many new Ad serotypes are originating in these patients. EKC is the most serious Ad-induced eye syndrome. It is highly contagious and may cause chronic vision problems that last for months to years. Though many serotypes of Ad have been implicated, types 8, 19, and 37 are most commonly associated with EKC. Knowledge of the relationship between Ad and human ocular tissues has been hampered by the fact that it has not been possible for human Ad to replicate and produce disease in the ocular tissue of animal models. The absence of laboratory models has also contributed to the slow progress in the development of effective treatment for human Ad ocular infections or their sequelae. The recent discovery of an animal model for human Ad induced pulmonary and ocular infections together with the availability of Ad mutants with specific genetic deletions, now make it possible to study the molecular mechanisms of pathogenesis of ocular Ad infection. The cotton rat, Sigmodon hispidus, provides an excellent and reproducible model for studying ocular Ad infections. The long-term objectives of this project are to elucidate at the molecular level the mechanism(s) of Ad pathogenesis in order to prevent or better control the ocular infections.
The specific aims of the proposal are: (1) Ad5 will be compared and contrasted with Ad8, a known ocular pathogen, in causing ocular disease in regards to the temporal course of viral spread, tissue involvement and immune response; (2) To determine the role of the viral E3 gene in ocular pathogenesis; (3) To determine the molecular mechanisms that induce the pathogenic process and characterize in vitro the role of Ad deletion mutations in the molecular changes induced by E3 gene product 19kd viral glycoprotein on the expression of class I MHC/H2 surface antigens of human and cotton rat ocular derived cells infected with Ad; (4) To test therapeutics and treatment regimens for these ocular infections in the laboratory. Virus isolates from infected animals treated with experimental chemotherapeutic drugs will be tested for the emergence of drug-resistance. The methodology to be used include basic virologic techniques, characterized human Ad type 5 E3 deletions mutants with molecular probes and monoclonal antibodies specific for Ad 5 gene products at the light microscopic and EM level with immunocytochemical stains.
