Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection
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Lin Xia1,3,*, Aimin Tang2,*, Weixu Meng1,*, Daniel C. Freed2, Linling He4, Dai Wang2, Fengsheng Li2, Leike Li1, Wei Xiong1, Xun Gui1, Robbie D. Schultz1, Haotai Chen1, Xi He2, Ryan Swoyer2, Sha Ha2, Yaping Liu2, Charles D. Morris4, Yu Zhou2, I-Ming Wang2, Qinjian Zhao3, Wenxin Luo3, Ningshao Xia3, Amy S. Espeseth2, Daria J. Hazuda2, Richard E. Rupp5, Alan D. Barrett5, Ningyan Zhang1, Jiang Zhu4,6,7, Tong-Ming Fu2 and Zhiqiang An1,3
1 Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
2 Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA
3 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, China
4 Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA
5 Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, USA
6 Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA
7 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
* These authors have contributed equally to this work
Jiang Zhu, email:
Tong-Ming Fu, email:
Zhiqiang An, email:
Keywords: human cytomegalovirus, human antibodies, B-cell repertoire, antiviral antibody, neutralization
Received: May 14, 2017 Accepted: May 19, 2017 Published: June 03, 2017
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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