Active evolution of memory B-cells specific to viral gH/gL/ pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection

Lin Xia, Aimin Tang, Weixu Meng, Daniel C. Freed, Linling He, Dai Wang, Fengsheng Li, Leike Li, Wei Xiong, Xun Gui, Robbie D. Schultz, Haotai Chen, Xi He, Ryan Swoyer, Sha Ha, Yaping Liu, Charles D. Morris, Yu Zhou, I. Ming Wang, Qinjian ZhaoWenxin Luo, Ningshao Xia, Amy S. Espeseth, Daria J. Hazuda, Richard Rupp, Alan Barrett, Ningyan Zhang, Jiang Zhu, Tong Ming Fu, Zhiqiang An

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)73654-73669
Number of pages16
JournalOncotarget
Volume8
Issue number43
DOIs
StatePublished - 2017

Fingerprint

Cytomegalovirus Infections
Healthy Volunteers
B-Lymphocytes
Infection
Vaccines
Antibodies
Tissue Donors
Antiviral Agents
Infection Control
Neutralizing Antibodies
Cytomegalovirus
Immunity
Viruses

Keywords

  • Antiviral antibody
  • B-cell repertoire
  • Human antibodies
  • Human cytomegalovirus
  • Neutralization

ASJC Scopus subject areas

  • Oncology

Cite this

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; Barrett, Alan; Zhang, Ningyan; Zhu, Jiang; Fu, Tong Ming; An, Zhiqiang.

In: Oncotarget, Vol. 8, No. 43, 2017, p. 73654-73669.

Research output: Contribution to journalArticle

Xia, L, Tang, A, Meng, W, Freed, DC, He, L, Wang, D, Li, F, Li, L, Xiong, W, Gui, X, Schultz, RD, Chen, H, He, X, Swoyer, R, Ha, S, Liu, Y, Morris, CD, Zhou, Y, Wang, IM, Zhao, Q, Luo, W, Xia, N, Espeseth, AS, Hazuda, DJ, Rupp, R, Barrett, A, Zhang, N, Zhu, J, Fu, TM & An, Z 2017, 'Active evolution of memory B-cells specific to viral gH/gL/ pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection', Oncotarget, vol. 8, no. 43, pp. 73654-73669. https://doi.org/10.18632/oncotarget.18359
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 ; Barrett, Alan ; 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. In: Oncotarget. 2017 ; Vol. 8, No. 43. pp. 73654-73669.
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abstract = "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.",
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AU - Xia, Lin

AU - Tang, Aimin

AU - Meng, Weixu

AU - Freed, Daniel C.

AU - He, Linling

AU - Wang, Dai

AU - Li, Fengsheng

AU - Li, Leike

AU - Xiong, Wei

AU - Gui, Xun

AU - Schultz, Robbie D.

AU - Chen, Haotai

AU - He, Xi

AU - Swoyer, Ryan

AU - Ha, Sha

AU - Liu, Yaping

AU - Morris, Charles D.

AU - Zhou, Yu

AU - Wang, I. Ming

AU - Zhao, Qinjian

AU - Luo, Wenxin

AU - Xia, Ningshao

AU - Espeseth, Amy S.

AU - Hazuda, Daria J.

AU - Rupp, Richard

AU - Barrett, Alan

AU - Zhang, Ningyan

AU - Zhu, Jiang

AU - Fu, Tong Ming

AU - An, Zhiqiang

PY - 2017

Y1 - 2017

N2 - 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.

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KW - Human antibodies

KW - Human cytomegalovirus

KW - Neutralization

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