Neutralization serotyping of BK polyomavirus infection in kidney transplant recipients.
Neutralization serotyping of BK polyomavirus infection in kidney transplant recipients.
复制标题
DOI：
10.1371/journal.ppat.1002650
复制
发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Buck CB
中科院分区：
文献类型：
--
作者：
Pastrana DV;Brennan DC;Cuburu N;Storch GA;Viscidi RP;Randhawa PS;Buck CB
BK多瘤病毒(BKV或BKPyV)相关的肾病影响多达10%的肾移植受者(KTRs)。BKV分离株分为四种基因型别。目前尚不清楚这四种基因型是否也是血清型。为了解决这个问题，我们开发了基于抗体介导的BKV I型和IV型报告载体(伪病毒)的高通量血清学检测方法。对用BKV-I或BKV-IV病毒样颗粒(VLP)免疫的小鼠的血清或自然感染的人的血清进行的中和试验表明，BKV-I特异性血清抗体对BKV-IV的中和能力较差，反之亦然。BKV-I和BKV-IV是不同的血清型，这一事实在传统的基于VLP的ELISA中不太明显。用BKV-I和BKV-IV中和试验检测移植后不同时间点KTRs的BKV型特异性中和抗体反应。在研究开始时，来自5%和49%的KTRs的血清分别没有检测到对BKV-I或BKV-IV的中和活性。到移植后一年，所有KDR的BKV-I中和血清阳性，最初BKV-IV血清阴性的受试者中有43%表现出BKV-IV中和急性血清转换的证据。结果提示了一种模型，在该模型中，BKV-IV特异性血清转换反映了最初缺乏能够中和IV型BKV的保护性抗体反应的KDR中的从头BKV-IV感染。如果这个模型是正确的，它表明预先给预期的KRR接种针对所有BKV血清型的基于VLP的多价疫苗，或者注射BKV中和抗体，可能会提供保护，防止移植物丢失或由于BKV相关性肾病而导致的功能障碍。血清学研究表明，几乎所有人都慢性感染BK多瘤病毒(BKV)。这种感染通常与明显的症状无关。然而，在治疗性免疫抑制的肾移植受者(KTRs)中，BKV的机会性复制可能导致移植肾功能障碍或丢失。BKV相关性肾病即使在抗BKV抗体水平较高的KDR中也可能发生，这种抗体可能会中和病毒。在这份报告中，我们提供了一个可能的解释：我们证明了至少有两种BKV基因类型，它们是关于抗体介导的中和作用的不同血清型。使用一种新的基于中和的方法，我们发现在移植时，108个KDR中约有一半没有检测到能够中和BKV IV型(BKV-IV)的抗体水平。在这些最初的BKV-IV幼稚KDR中，大约有一半在移植后第一年经历了BKV-IV特异性急性血清转换。这可能反映了来自移植肾的新生BKV-IV感染。在一项初步研究中，我们发现重组BKV-IV VLP可以在免疫动物中诱导高水平的BKV-IV中和抗体。我们的结果表明，给未来的KDR接种基于BKV VLP的疫苗可能会防止BKV机会性复制的发展。
BK polyomavirus (BKV or BKPyV) associated nephropathy affects up to 10% of kidney transplant recipients (KTRs). BKV isolates are categorized into four genotypes. It is currently unclear whether the four genotypes are also serotypes. To address this issue, we developed high-throughput serological assays based on antibody-mediated neutralization of BKV genotype I and IV reporter vectors (pseudoviruses). Neutralization-based testing of sera from mice immunized with BKV-I or BKV-IV virus-like particles (VLPs) or sera from naturally infected human subjects revealed that BKV-I specific serum antibodies are poorly neutralizing against BKV-IV and vice versa. The fact that BKV-I and BKV-IV are distinct serotypes was less evident in traditional VLP-based ELISAs. BKV-I and BKV-IV neutralization assays were used to examine BKV type-specific neutralizing antibody responses in KTRs at various time points after transplantation. At study entry, sera from 5% and 49% of KTRs showed no detectable neutralizing activity for BKV-I or BKV-IV neutralization, respectively. By one year after transplantation, all KTRs were neutralization seropositive for BKV-I, and 43% of the initially BKV-IV seronegative subjects showed evidence of acute seroconversion for BKV-IV neutralization. The results suggest a model in which BKV-IV-specific seroconversion reflects a de novo BKV-IV infection in KTRs who initially lack protective antibody responses capable of neutralizing genotype IV BKVs. If this model is correct, it suggests that pre-vaccinating prospective KTRs with a multivalent VLP-based vaccine against all BKV serotypes, or administration of BKV-neutralizing antibodies, might offer protection against graft loss or dysfunction due to BKV associated nephropathy. Serological studies have shown that nearly all humans are chronically infected with BK polyomavirus (BKV). The infection isn't usually associated with noticeable symptoms. However, opportunistic replication of BKV in therapeutically immunosuppressed kidney transplant recipients (KTRs) can lead to dysfunction or loss of the engrafted kidney. BKV associated nephropathy can occur even in KTRs with high levels of anti-BKV antibodies that might be expected to neutralize the virus. In this report we provide a possible explanation: we show there are at least two BKV genotypes, which are distinct serotypes with respect to antibody-mediated neutralization. Using a novel neutralization-based approach, we found that about half of 108 KTRs did not have detectable levels of antibodies capable of neutralizing BKV genotype IV (BKV-IV) at the time of transplantation. Of these initially BKV-IV naïve KTRs, about half experienced acute BKV-IV specific seroconversion during the first year after transplantation. This likely reflects a de novo BKV-IV infection arising from the engrafted kidney. In a pilot study, we show that recombinant BKV-IV VLPs can induce high levels of BKV-IV-neutralizing antibodies in vaccinated animals. Our results suggest that administration of a BKV VLP-based vaccine to prospective KTRs might protect against the development of opportunistic BKV replication.
登录
查看更多内容
影响因子：
4.8
作者：
Anzivino, Elena;Bellizzi, Anna;Pietropaolo, Valeria
通讯作者：
Pietropaolo, Valeria
影响因子：
9.4
作者：
HOGAN, TF;PADGETT, BL;MCBAIN, JA
通讯作者：
MCBAIN, JA
影响因子：
1.2
作者：
Cheerva, Alexandra C.;Raj, Ashok;Silverman, Craig L.
通讯作者：
Silverman, Craig L.
影响因子：
5.4
作者：
Buck, CB;Pastrana, DV;Schiller, JT
通讯作者：
Schiller, JT
影响因子：
30.3
作者：
Day PM;Kines RC;Thompson CD;Jagu S;Roden RB;Lowy DR;Schiller JT
通讯作者：
Schiller JT