This proposal uses the guinea pig as a model for the study of cytomegalovirus (CMV) infections in humans. The major emphasis of the project has been placed on elucidating, in guinea pigs, CMV induced pathogenic processes that are of clear clinical relevance to human CMV infections. These include infections associated with the mononucleosis syndrome, infections associated with interstitial pneumonia, infections of pregnant hosts and congenital infections. The research plan has been designed to elucidate in these disease entities (1) the state of the viral genome in tissues of acutely and chronically infected guinea pigs; (2) the cell populations that carry the viral genome and/or viral gene transcripts; and (3) the host defense mechanisms that participate in recovery from acute virus spread and in maintenance of CMV persistence. In addition to studies of mononucleosis syndrome and of interstitial pneumonia, the proposal includes experiments that will explore mechanisms of CMV reactivation during pregnancy, of transplacental CMV transfer and of congenital CMV infections following acquisition of CMV infection at various stages of gestation. The presence of infectious virus, viral antigen, viral genome and viral gene transcripts will be assessed in tissues obtained from acutely and persistently infected guinea pigs. Detection of guinea pig CMV-DNA and RNA transcripts will be carried out by in situ hybridization with whole genomic or subgenomic probes prepared from cloned fragments of guinea pig CMV-DNA. Specific cell populations will be identified by immunocytochemistry or histochemistry using available antigenic or enzyme markers. Experiments involving depletion, in vivo, of specific cell populations with monoclonal antibodies, or cell transfers of unseparated and selectively depleted cell populations will be initiated to investigate cellular elements operative in recovery from acute CMV infection and in maintenance of CMV persistence. The information obtained is expected to determine the presence of viral DNA and RNA in specific cells during acute and persistent CMV infections. In addition, virus host interactions at the local and systemic levels and mechanisms involved in the establishment of persistent infections will be elucidated. Considerable insight will be gained into important questions related to human CMV infections including transplacental transmission, mechanisms of reactivation and host defense processes.
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