Infections by human cytomegalovirus, such as CMV retinitis, account for one of the most important AIDS-associate opportunistic complications. Moreover, HCMV infections are also one of the most common causes of oral diseases associated with AIDS patients. HCMV infections in immunocompromised patients may produce oral lesions and painful ulcers and erosions have been reported on lips, tongue, and buccal mucosa. Salivary glands are a major source of persistent virus and have been shown to be a site for CMV latent infections. Viruses in saliva that are shed from infected salivary glands are believed to be one of the major sources for oral infections as well as for horizontal transmission. Understanding the mechanism of CMV infection in salivary glands as well as other parts of the oral cavity will provide insight into developing new drugs and novel strategies for treatment and prevention of CMV-associated oral diseases. Using murine cytomegalovirus as a model system, the proposed study is to identify the viral genes required for CMV replication in salivary glands and to study the functions of these viral determinants in supporting CMV infections in the oral cavity. The applicant has recently generated a pool of MCMV mutants that contain a transposon sequence and has isolated a viral mutant that was defective in replication in the salivary glands. In the proposed research, animals will be infected with viral mutants through direct inoculation to the salivary glands and those that are defective in replicating in the salivary glands will be isolated. Characterization of these mutants will be carried out to identify the genes that are mutated by the transposon insertion and their growth characteristics in tissue culture and in animals will be determined. Finally, the molecular mechanisms of how the identified viral determinants function in supporting MCMV infections in salivary glands will be studied. These studies will lead to the identification of viral genes required for CMV replication in salivary glands and the investigations of the functions of these genes in CMV infections of the oral cavity. Moreover, the results will provide insights into the mechanism of CMV pathogenesis and the development of novel strategies for treatment and prevention of CMV systemic infections as well as infections in the oral cavity.
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