Cytomegalovirus Virions Shed in Urine Have a Reversible Block to Epithelial Cell Entry and Are Highly Resistant to Antibody Neutralization

Abstract

ABSTRACT Cytomegalovirus (CMV) causes sensorineural hearing loss and developmental disabilities in newborns when infections are acquired in utero . Pregnant women may acquire CMV from oral exposure to CMV in urine or saliva from young children. Neutralizing antibodies in maternal saliva have the potential to prevent maternal infection and, in turn, fetal infection. As CMV uses different viral glycoprotein complexes to enter different cell types, the first cells to be infected in the oral cavity could determine the type of antibodies needed to disrupt oral transmission. Antibodies targeting the pentameric complex (PC) should block CMV entry into epithelial cells but not into fibroblasts or Langerhans cells (which do not require the PC for entry), while antibodies targeting glycoprotein complexes gB or gH/gL would be needed to block entry into fibroblasts, Langerhans cells, or other cell types. To assess the potential for antibodies to disrupt oral acquisition, CMV from culture-positive urine samples (uCMV) was used to study cell tropisms and sensitivity to antibody neutralization. uCMV entered epithelial cells poorly compared with the entry into fibroblasts. CMV-hyperimmune globulin or monoclonal antibodies targeting gB, gH/gL, or the PC were incapable of blocking the entry of uCMV into either fibroblasts or epithelial cells. Both phenotypes were lost after one passage in cultured fibroblasts, suggestive of a nongenetic mechanism. These results suggest that uCMV virions have a reversible block to epithelial cell entry. Antibodies may be ineffective in preventing maternal oral CMV acquisition but may limit viral spread in blood or tissues, thereby reducing or preventing fetal infection and disease.