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Figure 1: Schematic representation of pathways of CMV to the fetus and immune responses potentially important in transmission and prevention. The figure emphasizes the immunological milieu of pregnancy and some of the known immune adaptations associated with pregnancy. Left side of figure, CMV is known both to encode a plethora of immune evasion genes that subvert immune clearance of infection and to demonstrate substantial strain variation that can promote reinfection of already-immune hosts. Virus is believed to reach the placenta via the maternal compartment (a) or ascending infection via local extension in the reproductive tract (b). Although maternal antibody, CD4+, and CD8+ responses are generally intact in pregnancy, there are alterations in Th1/Th2 cytokine balance; alterations in NK cell subpopulations; increased Tregs; and modified cytokine responses. The uterine microenvironment in pregnancy may also play a role in direct local extension of CMV following virus exposure or reactivation (b), driven in part by increased localized IL-10 expression. Irrespective of the route of infection, the immunological profile of the placenta may either facilitate CMV transmission or inhibit it. Factors that may promote transmission include the less efficient killing potential of uNK cells; decreases in cytokines such as IL-12 and IF-γ; and the potential translocation of CMV particles across the syncytiotrophoblast if low avidity IgG is present. Factors that inhibit transmission include chemokines and β-defensins and, if present, high avidity neutralizing antibody, which may render virus noninfectious. Once virus enters the fetal compartment, the impaired capacity of fetal CD4+ to proliferate in response to CMV may impair immune control. The presence of transplacentally acquired IgG is believed to ameliorate the severity of disease. There is evidence that CD8+ cells, chemokines, and gammadelta T cells contribute to antiviral immunity in the fetal immune environment.