Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific
Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific
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DOI：
10.1128/jvi.01213-15
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发表时间：
2015-09-01
影响因子：
5.4
通讯作者：
Eisenberg, Roselyn J.
中科院分区：
文献类型：
--
作者：
Cairns, Tina M.;Huang, Zhen-Yu;Eisenberg, Roselyn J.
单纯疱疹病毒1型(HSV-1)和单纯疱疹病毒2型(HSV-2)可感染多种人类，并在感觉神经节形成潜伏感染。尽管一些感染者会周期性复发，但其他人不会。感染者产生细胞介导的和体液反应，包括产生针对病毒进入糖蛋白的病毒中和抗体(Abs)。此前，我们检查了10名HSV血清阳性个体的IgG；所有人都中和了病毒，主要针对GD或GD+GB。在这里，我们扩大了我们的研究范围，检查了另外32份来自HSV感染者的血清，其中23人没有复发疾病。使用Octet RED96系统，我们直接筛选了所有32份血清样本的糖蛋白结合和与已知的中和性抗-GD和-GB单抗(MAbs)的竞争。平均而言，复发队列与GD和GB的结合率较高，中和滴度也较高。在阻断关键的gD和gB表位的单抗方面也有类似的趋势。当我们耗尽六种抗体的特定糖蛋白时，我们发现了不同类型的反应，但总是主要针对GD和/或GB。有趣的是，在一名双重感染者中，对HSV-2的中和反应是由于GD2和GB2，而HSV-1的中和反应是由于Gd1和GB1。在另一种情况下，病毒中和是HSV-1特异性的，抗体反应完全针对GB1，尽管这种血清阻断类型-共同的抗-GD和-GB中和单抗。这些数据在未来的HSV疫苗设计中是相关的，因为它们证明了两种血清型的gD和gB作为免疫原的重要性。我们以前曾表明，感染HSV的人产生针对gD或gD+gB的中和抗体(在一个病例中，gD+gB+GC，这是HSV-1特异性的)。在这项更广泛的研究中，我们再次发现GD或GD+GB可以解释病毒的中和反应，这两种蛋白中的一种或两种的关键表位在自然感染的人的血清中都有表达。然而，我们也发现，一些人对国标本身产生了强烈的反应。此外，我们确定了GD和GB对HSV中和的特定类型的贡献。其他进入的糖蛋白Gc和Gh/gl的贡献很小，仅限于HSV-1的中和。了解人类看待和应对HSV的方式的变化对疫苗开发将是重要的。
Herpes simplex virus 1 (HSV-1) and HSV-2 infect many humans and establish a latent infection in sensory ganglia. Although some infected people suffer periodic recurrences, others do not. Infected people mount both cell-mediated and humoral responses, including the production of virus-neutralizing antibodies (Abs) directed at viral entry glycoproteins. Previously, we examined IgGs from 10 HSV-seropositive individuals; all neutralized virus and were directed primarily against gD or gD+gB. Here, we expand our studies and examine 32 additional sera from HSV-infected individuals, 23 of whom had no recurrent disease. Using an Octet RED96 system, we screened all 32 serum samples directly for both glycoprotein binding and competition with known neutralizing anti-gD and -gB monoclonal Abs (MAbs). On average, the recurrent cohort exhibited higher binding to gD and gB and had higher neutralization titers. There were similar trends in the blocking of MAbs to critical gD and gB epitopes. When we depleted six sera of Abs to specific glycoproteins, we found different types of responses, but always directed primarily at gD and/or gB. Interestingly, in one dual-infected person, the neutralizing response to HSV-2 was due to gD2 and gB2, whereas HSV-1 neutralization was due to gD1 and gB1. In another case, virus neutralization was HSV-1 specific, with the Ab response directed entirely at gB1, despite this serum blocking type-common anti-gD and -gB neutralizing MAbs. These data are pertinent in the design of future HSV vaccines since they demonstrate the importance of both serotypes of gD and gB as immunogens.IMPORTANCEWe previously showed that people infected with HSV produce neutralizing Abs directed against gD or a combination of gD+gB (and in one case, gD+gB+gC, which was HSV-1 specific). In this more extensive study, we again found that gD or gD+gB can account for the virus neutralizing response and critical epitopes of one or both of these proteins are represented in sera of naturally infected humans. However, we also found that some individuals produced a strong response against gB alone. In addition, we identified type-specific contributions to HSV neutralization from both gD and gB. Contributions from the other entry glycoproteins, gC and gH/gL, were minimal and limited to HSV-1 neutralization. Knowing the variations in how humans see and mount a response to HSV will be important to vaccine development.