Virus-leukocyte interactions are critical to the outcome of infections with potentially oncogenic viruses. Leukocytes limit the replication of both viruses and cells transformed by viruses. However, viruses may also replicate in leukocytes and alter their function, inhibiting an effective response. This proposal will study the interactions of potentially oncogenic human herpesviruses with human leukocytes. Cytomegalovirus is a major cause of human disease, as a teratogen, opportunistic pathogen following blood transfusions or immunosuppression, and as a possible oncogen. We have demonstrated that CMV has a potent immunosuppressive effect onleukocyte function. The mechanisms of this CMV-induced hyporesponsiveness will be explored. Functional evaluation of specific leukocyte subsets and their interactions will be undertaken in vivo and in vitro. Attempts will be made to correct or reconstruct CMV-induced defective leukocyte responses. CMV-leukocyte associations will also be exploited to help develop rapid diagnostic assays for CMV artigens in infected granulocytes. Herpes simplex virus may also have complex interactions with human leukocytes. We have established a model of herpes simplex virus persistent infection of human T lymphoblasts. This persistent infection can either be productive or non-productive, depending on manipulations in vitro. Addition of antiviral agents (antibody, interferon, acyclovir) or temperature elevation can result in non-productive infection. Removal of antivirals, lowering of temperature, addition of phytohemagglutinin or 5-azacytidine can induce productive infection. The mechanisms underlying these events will be explored in vitro, and attempts will be made to determine the importance of methylation in the maintenance of non-productive infections. In situ molecular hybridization techniques will be used to determine the numbers of cells that are infected during productive and non-productive infections. The same techniques will be used to investigate the recent suggestion that certain human diseases, e.g. Behcet's syndrome, are associated with lymphocytes carrying latent herpes simplex DNA. Our herpes model will also be used to explore interactions between antiviral agents and persistent infections.
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