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
Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, China.
Oncotarget. 2017 Jun 3;8(43):73654-73669. doi: 10.18632/oncotarget.18359. eCollection 2017 Sep 26.
Human cytomegalovirus (HCMV) can cause life-threatening infection in immunosuppressed patients, and 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.
人巨细胞病毒（HCMV）可在免疫抑制患者中引发危及生命的感染，并可能导致出生缺陷。目前尚无可用疫苗。健康受试者中的HCMV感染通常无症状，病毒会以潜伏感染的形式终身持续存在。宿主免疫可有效抵抗病毒再激活和另一种毒株的重复感染。因此，能够引发与自然感染相似免疫反应的候选疫苗可能具有保护作用。由于中和作用对预防性疫苗至关重要，了解抗病毒抗体在自然感染中的产生方式很重要。我们假设，通过使用单克隆抗体（mAb）的独特基因特征序列询问宿主B细胞库，可以揭示血清阳性受试者中抗体的发育路径。为实现这一目标，我们从三名具有不同中和效价的健康供体中分离出56种mAb。针对gH/gL/pUL128/130/131五聚体复合物的抗体在中和作用方面比针对gB的抗体更强效。使用这些mAb作为探针，在两名具有较高中和效价的供体中揭示了B细胞的扩展谱系发育模式和抗体活性成熟的证据。重要的是，这种模式仅限于针对五聚体的mAb，而针对gB的mAb则没有。因此，具有抗病毒功能（如中和作用）的记忆B细胞在两名供体的潜伏感染期间具有活性，这种活性导致了他们较高的中和效价。我们的结果表明，具有中和能力的记忆B细胞可能在宿主体内频繁被调动，可能是对沉默的病毒发作做出反应，这进一步表明中和抗体可能在控制复发性感染中发挥作用。
