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Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection
Human cytomegalovirus (HCMV) can cause life-threatening infection in immunosuppressed patients, and in utero infection that may lead to birth defects. No vaccine is currently available. HCMV infection in healthy subjects is generally asymptomatic, and virus persists as latent infection for life. Hos...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650289/ https://www.ncbi.nlm.nih.gov/pubmed/29088734 http://dx.doi.org/10.18632/oncotarget.18359 |
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author | Xia, Lin Tang, Aimin Meng, Weixu Freed, Daniel C. He, Linling Wang, Dai Li, Fengsheng Li, Leike Xiong, Wei Gui, Xun Schultz, Robbie D. Chen, Haotai He, Xi Swoyer, Ryan Ha, Sha Liu, Yaping Morris, Charles D. Zhou, Yu Wang, I-Ming Zhao, Qinjian Luo, Wenxin Xia, Ningshao Espeseth, Amy S. Hazuda, Daria J. Rupp, Richard E. Barrett, Alan D. Zhang, Ningyan Zhu, Jiang Fu, Tong-Ming An, Zhiqiang |
author_facet | Xia, Lin Tang, Aimin Meng, Weixu Freed, Daniel C. He, Linling Wang, Dai Li, Fengsheng Li, Leike Xiong, Wei Gui, Xun Schultz, Robbie D. Chen, Haotai He, Xi Swoyer, Ryan Ha, Sha Liu, Yaping Morris, Charles D. Zhou, Yu Wang, I-Ming Zhao, Qinjian Luo, Wenxin Xia, Ningshao Espeseth, Amy S. Hazuda, Daria J. Rupp, Richard E. Barrett, Alan D. Zhang, Ningyan Zhu, Jiang Fu, Tong-Ming An, Zhiqiang |
author_sort | Xia, Lin |
collection | PubMed |
description | Human cytomegalovirus (HCMV) can cause life-threatening infection in immunosuppressed patients, and in utero infection that may lead to birth defects. No vaccine is currently available. HCMV infection in healthy subjects is generally asymptomatic, and virus persists as latent infection for life. Host immunity is effective against reactivation and super-infection with another strain. Thus, vaccine candidates able to elicit immune responses similar to those of natural infection may confer protection. Since neutralization is essential for prophylactic vaccines, it is important to understand how antiviral antibodies are developed in natural infection. We hypothesized that the developmental path of antibodies in seropositive subjects could be unveiled by interrogating host B-cell repertoires using unique genetic signature sequences of mAbs. Towards this goal, we isolated 56 mAbs from three healthy donors with different neutralizing titers. Antibodies specific to the gH/gL/pUL128/130/131 pentameric complex were more potent in neutralization than those to gB. Using these mAbs as probes, patterns of extended lineage development for B-cells and evidence of active antibody maturation were revealed in two donors with higher neutralizing titers. Importantly, such patterns were limited to mAbs specific to the pentamer, but none to gB. Thus, memory B-cells with antiviral function such as neutralization were active during latent infection in the two donors, and this activity was responsible for their higher neutralizing titers. Our results indicated that memory B-cells of neutralizing capacity could be frequently mobilized in host, probably responding to silent viral episodes, further suggesting that neutralizing antibodies could play a role in control of recurrent infection. |
format | Online Article Text |
id | pubmed-5650289 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56502892017-10-30 Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection Xia, Lin Tang, Aimin Meng, Weixu Freed, Daniel C. He, Linling Wang, Dai Li, Fengsheng Li, Leike Xiong, Wei Gui, Xun Schultz, Robbie D. Chen, Haotai He, Xi Swoyer, Ryan Ha, Sha Liu, Yaping Morris, Charles D. Zhou, Yu Wang, I-Ming Zhao, Qinjian Luo, Wenxin Xia, Ningshao Espeseth, Amy S. Hazuda, Daria J. Rupp, Richard E. Barrett, Alan D. Zhang, Ningyan Zhu, Jiang Fu, Tong-Ming An, Zhiqiang Oncotarget Research Paper Human cytomegalovirus (HCMV) can cause life-threatening infection in immunosuppressed patients, and in utero infection that may lead to birth defects. No vaccine is currently available. HCMV infection in healthy subjects is generally asymptomatic, and virus persists as latent infection for life. Host immunity is effective against reactivation and super-infection with another strain. Thus, vaccine candidates able to elicit immune responses similar to those of natural infection may confer protection. Since neutralization is essential for prophylactic vaccines, it is important to understand how antiviral antibodies are developed in natural infection. We hypothesized that the developmental path of antibodies in seropositive subjects could be unveiled by interrogating host B-cell repertoires using unique genetic signature sequences of mAbs. Towards this goal, we isolated 56 mAbs from three healthy donors with different neutralizing titers. Antibodies specific to the gH/gL/pUL128/130/131 pentameric complex were more potent in neutralization than those to gB. Using these mAbs as probes, patterns of extended lineage development for B-cells and evidence of active antibody maturation were revealed in two donors with higher neutralizing titers. Importantly, such patterns were limited to mAbs specific to the pentamer, but none to gB. Thus, memory B-cells with antiviral function such as neutralization were active during latent infection in the two donors, and this activity was responsible for their higher neutralizing titers. Our results indicated that memory B-cells of neutralizing capacity could be frequently mobilized in host, probably responding to silent viral episodes, further suggesting that neutralizing antibodies could play a role in control of recurrent infection. Impact Journals LLC 2017-06-03 /pmc/articles/PMC5650289/ /pubmed/29088734 http://dx.doi.org/10.18632/oncotarget.18359 Text en Copyright: © 2017 Xia et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Xia, Lin Tang, Aimin Meng, Weixu Freed, Daniel C. He, Linling Wang, Dai Li, Fengsheng Li, Leike Xiong, Wei Gui, Xun Schultz, Robbie D. Chen, Haotai He, Xi Swoyer, Ryan Ha, Sha Liu, Yaping Morris, Charles D. Zhou, Yu Wang, I-Ming Zhao, Qinjian Luo, Wenxin Xia, Ningshao Espeseth, Amy S. Hazuda, Daria J. Rupp, Richard E. Barrett, Alan D. Zhang, Ningyan Zhu, Jiang Fu, Tong-Ming An, Zhiqiang Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection |
title | Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection |
title_full | Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection |
title_fullStr | Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection |
title_full_unstemmed | Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection |
title_short | Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection |
title_sort | active evolution of memory b-cells specific to viral gh/gl/pul128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650289/ https://www.ncbi.nlm.nih.gov/pubmed/29088734 http://dx.doi.org/10.18632/oncotarget.18359 |
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