Cytomegalovirus in the neonate: immune correlates of infection and protection

Abstract

Fetal and neonatal infections caused by human cytomegalovirus (CMV) are important causes of morbidity and occasional mortality. Development of a vaccine against congenital CMV infection is a major public health priority. Vaccine design is currently focused on strategies that aim to elicit neutralizing antibody and T-cell responses, toward the goal of preventing primary or recurrent infection in women of child-bearing age. However, there has been relatively little attention given to understanding the mechanisms of immune protection against acquisition of CMV infection in the fetus and newborn and how this information might be exploited for vaccine design. There has similarly been an insufficient study of what deficits in the immune response to CMV, both for mother and fetus, may increase susceptibility to congenital infection and disease. Protection of the fetus against vertical transmission can likely be achieved by protection of the placenta, which has its own unique immunological milieu, further complicating the analysis of the correlates of protective immunity. In this review, the current state of knowledge about immune effectors of protection against CMV in the maternal, placental, and fetal compartments is reviewed. A better understanding of immune responses that prevent and/or predispose to infection will help in the development of novel vaccine strategies.

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.