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Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies

Human cytomegalovirus (HCMV) infects 36% to almost 100% of adults and causes severe complications only in immunocompromised individuals. HCMV viral surface trimeric (gH/gL/gO) and pentameric (gH/gL/UL128/UL130/UL131A) complexes play important roles in HCMV infection and tropism. Here, we isolated an...

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Autores principales: Ai, Yuanbao, Wu, Changwen, Zhang, Ming, Jaijyan, Dabbu Kumar, Liu, Tong, Zan, Lipeng, Li, Nan, Yu, Wei, Wang, Yueming, Yuan, Xiaohui, Li, Chengming, Zheng, Weihong, Zhu, Hua, Liao, Hua-Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784774/
https://www.ncbi.nlm.nih.gov/pubmed/36342276
http://dx.doi.org/10.1128/spectrum.01393-22
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author Ai, Yuanbao
Wu, Changwen
Zhang, Ming
Jaijyan, Dabbu Kumar
Liu, Tong
Zan, Lipeng
Li, Nan
Yu, Wei
Wang, Yueming
Yuan, Xiaohui
Li, Chengming
Zheng, Weihong
Zhu, Hua
Liao, Hua-Xin
author_facet Ai, Yuanbao
Wu, Changwen
Zhang, Ming
Jaijyan, Dabbu Kumar
Liu, Tong
Zan, Lipeng
Li, Nan
Yu, Wei
Wang, Yueming
Yuan, Xiaohui
Li, Chengming
Zheng, Weihong
Zhu, Hua
Liao, Hua-Xin
author_sort Ai, Yuanbao
collection PubMed
description Human cytomegalovirus (HCMV) infects 36% to almost 100% of adults and causes severe complications only in immunocompromised individuals. HCMV viral surface trimeric (gH/gL/gO) and pentameric (gH/gL/UL128/UL130/UL131A) complexes play important roles in HCMV infection and tropism. Here, we isolated and identified a total of four neutralizing monoclonal antibodies (MAbs) derived from HCMV-seropositive blood donors. Based on their reactivity to HCMV trimer and pentamer, these MAbs can be divided into two groups. MAbs PC0012, PC0014, and PC0035 in group 1 bind both trimer and pentamer and neutralize CMV by interfering with the postattachment steps of CMV entering into cells. These three antibodies recognize antigenic epitopes clustered in a similar area, which are overlapped by the epitope recognized by the known neutralizing antibody MSL-109. MAb PC0034 in group 2 binds only to pentamer and neutralizes CMV by blocking the binding of pentamer to cells. Epitope mapping using pentamer mutants showed that amino acid T94 of the subunit UL128 and K27 of UL131A on the pentamer are key epitope-associated residues recognized by PC0034. This study provides new evidence and insight information on the importance of the development of the CMV pentamer as a CMV vaccine. In addition, these newly identified potent CMV MAbs can be attractive candidates for development as antibody therapeutics for the prevention and treatment of HCMV infection. IMPORTANCE The majority of the global population is infected with HCMV, but severe complications occur only in immunocompromised individuals. In addition, CMV infection is a major cause of birth defects in newborns. Currently, there are still no approved prophylactic vaccines or therapeutic monoclonal antibodies (MAbs) for clinical use against HCMV infection. This study identified and characterized a panel of four neutralizing MAbs targeting the HCMV pentamer complex with specific aims to identify a key protein(s) and antigenic epitopes in the HCMV pentamer complex. The study also explored the mechanism by which these newly identified antibodies neutralize HCMV in order to design better HCMV vaccines focusing on the pentamer and to provide attractive candidates for the development of effective cocktail therapeutics for the prevention and treatment of HCMV infection.
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spelling pubmed-97847742022-12-24 Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies Ai, Yuanbao Wu, Changwen Zhang, Ming Jaijyan, Dabbu Kumar Liu, Tong Zan, Lipeng Li, Nan Yu, Wei Wang, Yueming Yuan, Xiaohui Li, Chengming Zheng, Weihong Zhu, Hua Liao, Hua-Xin Microbiol Spectr Research Article Human cytomegalovirus (HCMV) infects 36% to almost 100% of adults and causes severe complications only in immunocompromised individuals. HCMV viral surface trimeric (gH/gL/gO) and pentameric (gH/gL/UL128/UL130/UL131A) complexes play important roles in HCMV infection and tropism. Here, we isolated and identified a total of four neutralizing monoclonal antibodies (MAbs) derived from HCMV-seropositive blood donors. Based on their reactivity to HCMV trimer and pentamer, these MAbs can be divided into two groups. MAbs PC0012, PC0014, and PC0035 in group 1 bind both trimer and pentamer and neutralize CMV by interfering with the postattachment steps of CMV entering into cells. These three antibodies recognize antigenic epitopes clustered in a similar area, which are overlapped by the epitope recognized by the known neutralizing antibody MSL-109. MAb PC0034 in group 2 binds only to pentamer and neutralizes CMV by blocking the binding of pentamer to cells. Epitope mapping using pentamer mutants showed that amino acid T94 of the subunit UL128 and K27 of UL131A on the pentamer are key epitope-associated residues recognized by PC0034. This study provides new evidence and insight information on the importance of the development of the CMV pentamer as a CMV vaccine. In addition, these newly identified potent CMV MAbs can be attractive candidates for development as antibody therapeutics for the prevention and treatment of HCMV infection. IMPORTANCE The majority of the global population is infected with HCMV, but severe complications occur only in immunocompromised individuals. In addition, CMV infection is a major cause of birth defects in newborns. Currently, there are still no approved prophylactic vaccines or therapeutic monoclonal antibodies (MAbs) for clinical use against HCMV infection. This study identified and characterized a panel of four neutralizing MAbs targeting the HCMV pentamer complex with specific aims to identify a key protein(s) and antigenic epitopes in the HCMV pentamer complex. The study also explored the mechanism by which these newly identified antibodies neutralize HCMV in order to design better HCMV vaccines focusing on the pentamer and to provide attractive candidates for the development of effective cocktail therapeutics for the prevention and treatment of HCMV infection. American Society for Microbiology 2022-11-07 /pmc/articles/PMC9784774/ /pubmed/36342276 http://dx.doi.org/10.1128/spectrum.01393-22 Text en Copyright © 2022 Ai et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Ai, Yuanbao
Wu, Changwen
Zhang, Ming
Jaijyan, Dabbu Kumar
Liu, Tong
Zan, Lipeng
Li, Nan
Yu, Wei
Wang, Yueming
Yuan, Xiaohui
Li, Chengming
Zheng, Weihong
Zhu, Hua
Liao, Hua-Xin
Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies
title Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies
title_full Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies
title_fullStr Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies
title_full_unstemmed Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies
title_short Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies
title_sort neutralization epitopes in trimer and pentamer complexes recognized by potent cytomegalovirus-neutralizing human monoclonal antibodies
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784774/
https://www.ncbi.nlm.nih.gov/pubmed/36342276
http://dx.doi.org/10.1128/spectrum.01393-22
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