HCMV trimer- and pentamer-specific antibodies synergize for virus neutralization but do not correlate with congenital transmission

Adam Vanarsdall, Andrea L. Chin, Jing Liu, Theodore S. Jardetzky, James Mudd, Susan Orloff, Daniel Streblow, Marisa M. Mussi-Pinhata, Aparecida Y. Yamamoto, Geraldo Duarte, William J. Britt, David Johnson

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Human cytomegalovirus (HCMV) causes substantial disease in transplant patients and harms the development of the nervous system in babies infected in utero. Thus, there is a major focus on developing safe and effective HCMV vaccines. Evidence has been presented that a major target of neutralizing antibodies (NAbs) is the HCMV pentamer glycoprotein gH/gL/UL128-131. In some studies, most of the NAbs in animal or human sera were found to recognize the pentamer, which mediates HCMV entry into endothelial and epithelial cells. It was also reported that pentamer-specific antibodies correlate with protection against transmission from mothers to babies. One problem with the studies on pentamer-specific NAbs to date has been that the studies did not compare the pentamer to the other major form of gH/gL, the gH/gL/gO trimer, which is essential for entry into all cell types. Here, we demonstrate that both trimer and pentamer NAbs are frequently found in human transplant patients’ and pregnant mothers’ sera. Depletion of human sera with trimer caused reductions in NAbs similar to that observed following depletion with the pentamer. The trimer- and pentamer-specific antibodies acted in a synergistic fashion to neutralize HCMV and also to prevent virus cell-to-cell spread. Importantly, there was no correlation between the titers of trimer- and pentamer-specific NAbs and transmission of HCMV from mothers to babies. Therefore, both the trimer and pentamer are important targets of NAbs. Nevertheless, these antibodies do not protect against transmission of HCMV from mothers to babies.

Original languageEnglish (US)
Pages (from-to)3728-3733
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number9
DOIs
StatePublished - Feb 26 2019

Fingerprint

Cytomegalovirus
Neutralizing Antibodies
Viruses
Antibodies
Mothers
Cytomegalovirus Vaccines
Serum
Patient Harm
Transplants
Nervous System
Endothelial Cells
Epithelial Cells

Keywords

  • Cell-to-cell spread
  • Congenital
  • Neutralizing antibodie
  • Transplant
  • Vaccines

ASJC Scopus subject areas

  • General

Cite this

HCMV trimer- and pentamer-specific antibodies synergize for virus neutralization but do not correlate with congenital transmission. / Vanarsdall, Adam; Chin, Andrea L.; Liu, Jing; Jardetzky, Theodore S.; Mudd, James; Orloff, Susan; Streblow, Daniel; Mussi-Pinhata, Marisa M.; Yamamoto, Aparecida Y.; Duarte, Geraldo; Britt, William J.; Johnson, David.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 9, 26.02.2019, p. 3728-3733.

Research output: Contribution to journalArticle

Vanarsdall, Adam ; Chin, Andrea L. ; Liu, Jing ; Jardetzky, Theodore S. ; Mudd, James ; Orloff, Susan ; Streblow, Daniel ; Mussi-Pinhata, Marisa M. ; Yamamoto, Aparecida Y. ; Duarte, Geraldo ; Britt, William J. ; Johnson, David. / HCMV trimer- and pentamer-specific antibodies synergize for virus neutralization but do not correlate with congenital transmission. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 9. pp. 3728-3733.
@article{566bda4b9b784a3e8ae7b7b11043fbbb,
title = "HCMV trimer- and pentamer-specific antibodies synergize for virus neutralization but do not correlate with congenital transmission",
abstract = "Human cytomegalovirus (HCMV) causes substantial disease in transplant patients and harms the development of the nervous system in babies infected in utero. Thus, there is a major focus on developing safe and effective HCMV vaccines. Evidence has been presented that a major target of neutralizing antibodies (NAbs) is the HCMV pentamer glycoprotein gH/gL/UL128-131. In some studies, most of the NAbs in animal or human sera were found to recognize the pentamer, which mediates HCMV entry into endothelial and epithelial cells. It was also reported that pentamer-specific antibodies correlate with protection against transmission from mothers to babies. One problem with the studies on pentamer-specific NAbs to date has been that the studies did not compare the pentamer to the other major form of gH/gL, the gH/gL/gO trimer, which is essential for entry into all cell types. Here, we demonstrate that both trimer and pentamer NAbs are frequently found in human transplant patients’ and pregnant mothers’ sera. Depletion of human sera with trimer caused reductions in NAbs similar to that observed following depletion with the pentamer. The trimer- and pentamer-specific antibodies acted in a synergistic fashion to neutralize HCMV and also to prevent virus cell-to-cell spread. Importantly, there was no correlation between the titers of trimer- and pentamer-specific NAbs and transmission of HCMV from mothers to babies. Therefore, both the trimer and pentamer are important targets of NAbs. Nevertheless, these antibodies do not protect against transmission of HCMV from mothers to babies.",
keywords = "Cell-to-cell spread, Congenital, Neutralizing antibodie, Transplant, Vaccines",
author = "Adam Vanarsdall and Chin, {Andrea L.} and Jing Liu and Jardetzky, {Theodore S.} and James Mudd and Susan Orloff and Daniel Streblow and Mussi-Pinhata, {Marisa M.} and Yamamoto, {Aparecida Y.} and Geraldo Duarte and Britt, {William J.} and David Johnson",
year = "2019",
month = "2",
day = "26",
doi = "10.1073/pnas.1814835116",
language = "English (US)",
volume = "116",
pages = "3728--3733",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "9",

}

TY - JOUR

T1 - HCMV trimer- and pentamer-specific antibodies synergize for virus neutralization but do not correlate with congenital transmission

AU - Vanarsdall, Adam

AU - Chin, Andrea L.

AU - Liu, Jing

AU - Jardetzky, Theodore S.

AU - Mudd, James

AU - Orloff, Susan

AU - Streblow, Daniel

AU - Mussi-Pinhata, Marisa M.

AU - Yamamoto, Aparecida Y.

AU - Duarte, Geraldo

AU - Britt, William J.

AU - Johnson, David

PY - 2019/2/26

Y1 - 2019/2/26

N2 - Human cytomegalovirus (HCMV) causes substantial disease in transplant patients and harms the development of the nervous system in babies infected in utero. Thus, there is a major focus on developing safe and effective HCMV vaccines. Evidence has been presented that a major target of neutralizing antibodies (NAbs) is the HCMV pentamer glycoprotein gH/gL/UL128-131. In some studies, most of the NAbs in animal or human sera were found to recognize the pentamer, which mediates HCMV entry into endothelial and epithelial cells. It was also reported that pentamer-specific antibodies correlate with protection against transmission from mothers to babies. One problem with the studies on pentamer-specific NAbs to date has been that the studies did not compare the pentamer to the other major form of gH/gL, the gH/gL/gO trimer, which is essential for entry into all cell types. Here, we demonstrate that both trimer and pentamer NAbs are frequently found in human transplant patients’ and pregnant mothers’ sera. Depletion of human sera with trimer caused reductions in NAbs similar to that observed following depletion with the pentamer. The trimer- and pentamer-specific antibodies acted in a synergistic fashion to neutralize HCMV and also to prevent virus cell-to-cell spread. Importantly, there was no correlation between the titers of trimer- and pentamer-specific NAbs and transmission of HCMV from mothers to babies. Therefore, both the trimer and pentamer are important targets of NAbs. Nevertheless, these antibodies do not protect against transmission of HCMV from mothers to babies.

AB - Human cytomegalovirus (HCMV) causes substantial disease in transplant patients and harms the development of the nervous system in babies infected in utero. Thus, there is a major focus on developing safe and effective HCMV vaccines. Evidence has been presented that a major target of neutralizing antibodies (NAbs) is the HCMV pentamer glycoprotein gH/gL/UL128-131. In some studies, most of the NAbs in animal or human sera were found to recognize the pentamer, which mediates HCMV entry into endothelial and epithelial cells. It was also reported that pentamer-specific antibodies correlate with protection against transmission from mothers to babies. One problem with the studies on pentamer-specific NAbs to date has been that the studies did not compare the pentamer to the other major form of gH/gL, the gH/gL/gO trimer, which is essential for entry into all cell types. Here, we demonstrate that both trimer and pentamer NAbs are frequently found in human transplant patients’ and pregnant mothers’ sera. Depletion of human sera with trimer caused reductions in NAbs similar to that observed following depletion with the pentamer. The trimer- and pentamer-specific antibodies acted in a synergistic fashion to neutralize HCMV and also to prevent virus cell-to-cell spread. Importantly, there was no correlation between the titers of trimer- and pentamer-specific NAbs and transmission of HCMV from mothers to babies. Therefore, both the trimer and pentamer are important targets of NAbs. Nevertheless, these antibodies do not protect against transmission of HCMV from mothers to babies.

KW - Cell-to-cell spread

KW - Congenital

KW - Neutralizing antibodie

KW - Transplant

KW - Vaccines

UR - http://www.scopus.com/inward/record.url?scp=85062026396&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062026396&partnerID=8YFLogxK

U2 - 10.1073/pnas.1814835116

DO - 10.1073/pnas.1814835116

M3 - Article

C2 - 30733288

AN - SCOPUS:85062026396

VL - 116

SP - 3728

EP - 3733

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 9

ER -