This proposal uses the guinea pig as an animal model for the study of human congenital cytomegalovirus (CMV) infection. The project will study the effects of CMV infection occurring at different stages of pregnancy on the development and functions of the immune system in the progeny. We will test the following hypotheses: (1) CMV infection of the fetal host alters its immune maturation resulting in immune dysfunctions in the progeny; (2) these immune alterations in turn modulate the virulence of CMV during congenital infection; (3) the occurrence of immune dysfunction and the severity of disease during congenital CMV infection depend on the time at which the fetus is infected in vitro. Experimental primary infection, reinfection, or reactivation of infection will be produced in guinea pigs during early, middle or late gestation. The histology of lymphoid tissues, proportions of lymphocytes and host immune responses to CMV, to other antigens and to mitogens will be assessed in the fetuses at various gestational sges, in neonates, and in the adult progeny, age 1 to 12 months. Humoral antibody and antibody forming cell responses, delayed hypersensitivity reactions and cellular proliferative and cy totoxic responses will be evaluated. Results on immune responses in offspring of infected mothers will be compared to offspring of uninfected mothers and correlated with the localization of infectius virus, viral antigen and tissue lesions in the brain and other tissues of the progeny. The information obtained is expected to determine the precise role of the time of fetal infection on the virulence of CMV and on the occurrence of immune dysfunctions duirng congenital CMV infection. In addition, the critical host defense functions which participate in recovery and resistance to congenital CMV infection will be elucidated. Clarification of these processes in guinea pigs will contribute to the understanding and to the control of prenatal human CMV infection.