Fetal Human Cytomegalovirus Transmission Correlates With Delayed Maternal Antibodies to gH/gL/pUL128-130-131 Complex During Primary Infection

PLoS One. 2013;8(3):e59863. doi: 10.1371/journal.pone.0059863. Epub 2013 Mar 29.

Abstract

Primary human cytomegalovirus (HCMV) infections during pregnancy are associated with a high risk of virus transmission to the fetus. To identify correlates of intrauterine HCMV transmission, serial serum samples from HCMV transmitter and non-transmitter pregnant women with primary HCMV infection were analyzed for the presence of neutralizing antibodies against different glycoproteins and glycoprotein complexes, which are known to mediate entry into distinct types of host cells. Neutralizing activity was detected in the sera early after primary infection; absorption with a soluble pentameric complex formed by gH/gL/pUL128-131, but not with gH/gL dimer or with gB, abolished the capacity of sera to neutralize infection of epithelial cells. Importantly, an early, high antibody response to pentamer antigenic sites was associated with a significantly reduced risk of HCMV transmission to the fetus. This association is consistent with the high in vitro inhibition of HCMV infection of epithelial/endothelial cells as well as cell-to-cell spreading and virus transfer to leukocytes by anti-pentamer antibodies. Taken together, these findings indicate that the HCMV pentamer complex is a major target of the antibody-mediated maternal immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / blood
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / blood*
  • Antibodies, Viral / immunology
  • Binding, Competitive
  • Cytomegalovirus
  • Cytomegalovirus Infections / immunology
  • Cytomegalovirus Infections / transmission*
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / cytology
  • Female
  • Glycoproteins / immunology
  • Humans
  • Immunity, Humoral
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Infectious Disease Transmission, Vertical*
  • Membrane Glycoproteins / immunology*
  • Neutralization Tests
  • Pregnancy
  • Pregnancy Complications, Infectious / immunology*
  • Pregnancy Complications, Infectious / virology
  • Protein Binding
  • Regression Analysis
  • Viral Envelope Proteins / immunology*
  • Viral Proteins / immunology

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Glycoproteins
  • Immunoglobulin G
  • Membrane Glycoproteins
  • UL115 protein, Human herpesvirus 5
  • UL128 protein, human cytomegalovirus
  • Viral Envelope Proteins
  • Viral Proteins
  • glycoprotein H, Cytomegalovirus

Grant support

This work was partially supported by the Fondazione CARIPLO, Milan, Italy, grant 93043/A (to G. Gerna), by the Ministero della Salute, Ricerca Corrente Fondazione IRCCS Policlinico San Matteo grants 80206 (to E. Percivalle) and 80513 (to MG. Revello), and by the Fondazione Carlo Denegri (FCD), Torino, Italy (to G. Gerna). A.Lanzavecchia is supported by the Helmut Horten Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.