Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection.
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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沉默人类巨细胞病毒感染的健康受试者中针对病毒 gH/gL/pUL128/130/131 五聚体复合物的记忆 B 细胞的主动进化
DOI：
10.18632/oncotarget.18359
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发表时间：
2017-09-26
期刊：
影响因子：
--
通讯作者：
An Z
中科院分区：
文献类型：
--
作者：
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 RE;Barrett AD;Zhang N;Zhu J;Fu TM;An Z
人巨细胞病毒(HCMV)可在免疫抑制患者中引起危及生命的感染，在宫内感染可能导致出生缺陷。目前还没有疫苗可用。健康人巨细胞病毒感染一般无症状，病毒以潜伏感染的形式终生存在。宿主免疫对另一种毒株的重新激活和重复感染有效。因此，能够引起与自然感染相似的免疫反应的候选疫苗可能会提供保护。由于中和对于预防性疫苗至关重要，因此了解抗病毒抗体在自然感染中是如何产生的是很重要的。我们假设，通过使用mAbs独特的遗传签名序列询问宿主B细胞谱系，可以揭示血清阳性对象中抗体的发育路径。为此，我们从三个中和效价不同的健康供者身上分离出56株单抗。抗Gh/gl/pUL128/130/131五聚体的抗体中和能力强于抗GB的抗体。以这些单抗为探针，在两个中和效价较高的供者中，发现了B细胞的扩展谱系发育模式和活性抗体成熟的证据。重要的是，这种模式仅限于五聚体特异性单抗，而不是GB单抗。因此，在两个捐献者中，具有中和等抗病毒功能的记忆B细胞在潜伏感染期间是活跃的，这是导致其中和效价较高的原因。我们的结果表明，具有中和能力的记忆B细胞可以在宿主中频繁动员，可能对沉默的病毒发作有反应，进一步表明中和抗体可能在控制反复感染中发挥作用。
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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