Emerging Concepts in Congenital Cytomegalovirus

Abstract

Over a century of research has focused on improving our understanding of congenital cytomegalovirus (cCMV), yet it remains the most common congenital infection in the United States, affecting 3 to 6 per 1000 live born infants each year. Pregnancies affected by cCMV are at a heightened risk of spontaneous abortion and intrauterine fetal demise. Neonates born with cCMV are also at substantial risk for long-term neurodevelopmental sequelae and disability, including sensorineural hearing loss, even those born without clinically apparent disease. Considerable progress has been made in recent years in study of the epidemiology and transmission of cCMV, developing better diagnostic strategies, implementing newborn screening programs, improving therapeutics, and launching vaccine trials. In this article, we review recent developments in the understanding of the virology and immunobiology of cytomegalovirus. We further discuss how this knowledge informs our understanding of the pathophysiology of cCMV and directs strategies aimed at improving outcomes and quality of life for congenitally infected children. We also provide an update on the epidemiology of cCMV in the United States, evolving scientific understanding of maternal-fetal transmission, enhanced screening approaches, and recognition of neonatal and long-term sequelae. Finally, we review the current landscape of pediatric cCMV research and provide recommendations for novel and high-priority areas for future investigation.

Fig. 1.

Structure and isomerization of HCMV genome. Representation of the HCMV genome (not on scale) with its four possible isomers (panels a–d). In panel a, the orientation of U_L and U_S is based on U_L- and U_S- orientation of the HCMV wild-type reference Merlin (GenBank AY446894). Panels b–d correspond to the other three possible isomer orientations. Genome regions that are characteristic for HCMV: IR_L, IR_S, TR_L, TR_S, OriLyt repetition (OriLytRep) and a′ are colored in red, purple, gray, green, black and yellow, respectively. Small black arrows correspond to the direction of selected ORFs (UL1, UL145, US1 and US34) which help to illustrate the orientation of the unique regions (big black arrow) between the different isomers. Dashed gray lines connect the specific a′ sequences that contributed to the isomerization.

Figure 2.

Typical fetal brain development and potential sequelae of congenital cytomegalovirus infection

Fig. 3.

CMV virion demonstrating key envelope glycoproteins and glycoprotein complexes important in protective immunity that stand as potential subunit vaccine candidates. Viral envelope, tegument, and nucleocapsid are as indicated. Glycoprotein complexes are labelled; see Table 1 for additional details.