Human cytomegalovirus (hCMV) is the most common cause of perinatal viral infection in the United States. Morbidity associated with this illness often results in lifelong disability. Although much is known about the molecular biology of hCMV, the study of congenital infection in animal models has been hindered by the species-specificity of cytomegaloviruses. in contrast to other small animal models of CMV, the guinea pig cytomegalovirus (gpCMV) causes infection in utero. Unfortunately, little is known about gpCMV gene products. These studies propose to identify and characterize three gpCMV genes likely to be critically involved in regulation of viral gene expression and host response to infection: the major immediate early gene (MIE), the transactivator protein pp71, and the envelope glycoprotein, gH. MIE gene activity is the most important factor regulating hCMV replication. Transcriptional activity from this locus may be a critical determinant dictating tissue distribution of virus in vivo, establishment of or reactivation from latency, and teratogenesis. A reporter gene assay system will be established to facilitate a molecular dissection of the critical cis and trans elements regulating expression from the gpCMV MIE locus. To map the role of specific viral genes on the in vivo pathogenesis of CMV, targeted mutations in key regulatory genes will be introduced into the viral genome by homologous recombination, and the phenotype of mutant virus examined in animals. As a prerequisite to vaccine studies targeted at preventing congenital CMV infection, the cloned gH will be expressed in fusion protein systems and evaluated for immunogenicity in guinea pigs. The applicant, whose primary expertise is in the field of molecular biology, will be working under the guidance of Dr. Lawrence Stanberry, the primary sponsor, who is an internationally recognized expert in the study of pathogenesis of herpesvirus infections in animal model systems. The Children's Hospital Research Foundation in Cincinnati, Ohio, is uniquely well suited to the multidisciplinary evaluation of pathogenesis, basic and molecular virology, and vaccine testing in animal models. The long term goals of this proposed work are twofold: l) to use this unique animal model of congenital CMV infection to address questions about the role of specific viral genes in pathogenesis and 2) to use the data derived from the molecular characterization of gpCMV to test hypotheses about vaccine intervention strategies.
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