Characterization of Plasma Immunoglobulin G Responses in Elite Neutralizers of Human Cytomegalovirus.
elite neutralizers
human cytomegalovirus
neutralizing antibodies
polyfunctional antibodies
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
01 11 2022
01 11 2022
Historique:
received:
06
05
2022
accepted:
11
08
2022
pubmed:
16
8
2022
medline:
4
11
2022
entrez:
15
8
2022
Statut:
ppublish
Résumé
Human cytomegalovirus (HCMV) is the most common infectious complication of organ transplantation and cause of birth defects worldwide. There are limited therapeutic options and no licensed vaccine to prevent HCMV infection or disease. To inform development of HCMV antibody-based interventions, a previous study identified individuals with potent and broad plasma HCMV-neutralizing activity, termed elite neutralizers (ENs), from a cohort of HCMV-seropositive (SP) blood donors. However, the specificities and functions of plasma antibodies associated with EN status remained undefined. We sought to determine the plasma antibody specificities, breadth, and Fc-mediated antibody effector functions associated with the most potent HCMV-neutralizing responses in plasma from ENs (n = 25) relative to that from SP donors (n = 19). We measured antibody binding against various HCMV strains and glycoprotein targets and evaluated Fc-mediated effector functions, antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). We demonstrate that ENs have elevated immunoglobulin G binding responses against multiple viral glycoproteins, relative to SP donors. Our study also revealed potent HCMV-specific antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis activity of plasma from ENs. We conclude that antibody responses against multiple glycoprotein specificities may be needed to achieve potent plasma neutralization and that potently HCMV elite-neutralizing plasma antibodies can also mediate polyfunctional responses.
Sections du résumé
BACKGROUND
Human cytomegalovirus (HCMV) is the most common infectious complication of organ transplantation and cause of birth defects worldwide. There are limited therapeutic options and no licensed vaccine to prevent HCMV infection or disease. To inform development of HCMV antibody-based interventions, a previous study identified individuals with potent and broad plasma HCMV-neutralizing activity, termed elite neutralizers (ENs), from a cohort of HCMV-seropositive (SP) blood donors. However, the specificities and functions of plasma antibodies associated with EN status remained undefined.
METHODS
We sought to determine the plasma antibody specificities, breadth, and Fc-mediated antibody effector functions associated with the most potent HCMV-neutralizing responses in plasma from ENs (n = 25) relative to that from SP donors (n = 19). We measured antibody binding against various HCMV strains and glycoprotein targets and evaluated Fc-mediated effector functions, antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).
RESULTS
We demonstrate that ENs have elevated immunoglobulin G binding responses against multiple viral glycoproteins, relative to SP donors. Our study also revealed potent HCMV-specific antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis activity of plasma from ENs.
CONCLUSIONS
We conclude that antibody responses against multiple glycoprotein specificities may be needed to achieve potent plasma neutralization and that potently HCMV elite-neutralizing plasma antibodies can also mediate polyfunctional responses.
Identifiants
pubmed: 35970817
pii: 6667625
doi: 10.1093/infdis/jiac341
pmc: PMC10205896
doi:
Substances chimiques
Immunoglobulin G
0
Antibodies, Neutralizing
0
Antibodies, Viral
0
Viral Envelope Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1667-1677Subventions
Organisme : NIAID NIH HHS
ID : P01 AI129859
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI052077
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007171
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM145449
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Déclaration de conflit d'intérêts
Potential conflicts of interest. S. R. P. is a consultant for Moderna, Merck, Pfizer, GlaxoSmithKline, Dynavax, and Hoopika cytomegalovirus (CMV) vaccine programs and leads sponsored research programs with Moderna and Merck. She also serves on the board of the National CMV Foundation and as an educator on CMV for Medscape. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Références
Viruses. 2021 Jun 09;13(6):
pubmed: 34207868
J Virol. 2012 Jul;86(13):7444-7
pubmed: 22532696
Sci Transl Med. 2020 Nov 4;12(568):
pubmed: 33148624
Vaccine. 2016 Jan 12;34(3):313-9
pubmed: 26657184
Nature. 2012 Nov 15;491(7424):406-12
pubmed: 23151583
Ann Transplant. 2016 Sep 06;21:558-64
pubmed: 27595792
J Infect Dis. 2018 May 25;217(12):1907-1917
pubmed: 29528415
Transfusion. 2017 Feb;57(2):412-422
pubmed: 27861998
Trends Microbiol. 2020 Nov;28(11):900-912
pubmed: 32448762
J Infect. 2016 May;72(5):597-607
pubmed: 26920791
PLoS Pathog. 2017 Apr 12;13(4):e1006281
pubmed: 28403202
J Infect Dis. 2019 Jul 31;220(5):772-780
pubmed: 31107951
PLoS Pathog. 2014 Nov 20;10(11):e1004524
pubmed: 25412505
J Clin Pathol. 2001 Feb;54(2):84-8
pubmed: 11215290
PLoS Pathog. 2015 Oct 20;11(10):e1005227
pubmed: 26484870
Front Microbiol. 2019 May 15;10:1005
pubmed: 31156572
Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6273-6278
pubmed: 29686064
Clin Infect Dis. 2004 Jul 15;39(2):155-61
pubmed: 15307021
N Engl J Med. 2012 Apr 5;366(14):1275-86
pubmed: 22475592
PLoS Pathog. 2016 Apr 15;12(4):e1005564
pubmed: 27082872
J Immunol Methods. 2003 Oct 1;281(1-2):65-78
pubmed: 14580882
Nat Microbiol. 2016 Jun 06;1(8):16082
pubmed: 27573107
Rev Med Virol. 2010 Jul;20(4):202-13
pubmed: 20564615
PLoS One. 2013;8(3):e59863
pubmed: 23555812
PLoS Pathog. 2011 Aug;7(8):e1002172
pubmed: 21852946
J Virol. 2010 Jan;84(2):1005-13
pubmed: 19889756
J Immunol Methods. 2004 Nov;294(1-2):15-22
pubmed: 15604012
Rev Med Virol. 2019 May;29(3):e2034
pubmed: 30706584
J Infect Dis. 2018 Aug 14;218(6):876-885
pubmed: 29684155
Virology. 2020 Sep;548:182-191
pubmed: 32838941
Science. 2019 Jan 18;363(6424):288-293
pubmed: 30655443
Antimicrob Agents Chemother. 2015 Aug;59(8):4919-29
pubmed: 26055360
Fetal Diagn Ther. 2019;45(2):111-117
pubmed: 29684915
PLoS One. 2019 Apr 10;14(4):e0213409
pubmed: 30969970
N Engl J Med. 2009 Mar 19;360(12):1191-9
pubmed: 19297572
Lancet. 2011 Apr 9;377(9773):1256-63
pubmed: 21481708
J Infect Dis. 2016 Dec 15;214(12):1916-1923
pubmed: 27923951
Ital J Pediatr. 2017 Apr 17;43(1):38
pubmed: 28416012
J Gen Virol. 1992 Sep;73 ( Pt 9):2375-83
pubmed: 1383409
N Engl J Med. 2014 Apr 3;370(14):1316-26
pubmed: 24693891
N Engl J Med. 2005 Sep 29;353(13):1350-62
pubmed: 16192480
J Gen Virol. 2006 Jul;87(Pt 7):1763-1779
pubmed: 16760381
Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6267-6272
pubmed: 29712861