Bellizzi Anna, Anzivino Elena, Rodio Donatella Maria, Cioccolo Sara, Scrivo Rossana, Morreale Manuela, Pontecorvo Simona, Ferrari Federica, Di Nardo Giovanni, Nencioni Lucia, Carluccio Silvia, Valesini Guido, Francia Ada, Cucchiara Salvatore, Palamara Anna Teresa, Pietropaolo Valeria
Department of Public Health and Infectious Diseases, Sapienza University, P,le Aldo Moro, 5, 00185 Rome, Italy.
Virol J. 2013 Sep 30;10:298. doi: 10.1186/1743-422X-10-298.
Progressive multifocal leukoencephalopathy (PML) onset, caused by Polyomavirus JC (JCPyV) in patients affected by immune-mediated diseases during biological treatment, raised concerns about the safety profile of these agents. Therefore, the aims of this study were the JCPyV reactivation monitoring and the noncoding control region (NCCR) and viral protein 1 (VP1) analysis in patients affected by different immune-mediated diseases and treated with biologics.
We performed JCPyV-specific quantitative PCR of biological samples collected at moment of recruitment (t0) and every 4 months (t1, t2, t3, t4). Subsequently, rearrangements' analysis of NCCR and VP1 was carried out. Data were analyzed using χ2 test.
Results showed that at t0 patients with chronic inflammatory rheumatic diseases presented a JCPyV load in the urine significantly higher (p≤0.05) than in patients with multiple sclerosis (MS) and Crohn's disease (CD). It can also be observed a significant association between JC viruria and JCPyV antibodies after 1 year of natalizumab (p=0.04) in MS patients. Finally, NCCR analysis showed the presence of an archetype-like sequence in all urine samples, whereas a rearranged NCCR Type IR was found in colon-rectal biopsies collected from 2 CD patients after 16 months of infliximab. Furthermore, sequences isolated from peripheral blood mononuclear cells (PBMCs) of 2 MS patients with JCPyV antibody at t0 and t3, showed a NCCR Type IIR with a duplication of a 98 bp unit and a 66 bp insert, resulting in a boxB deletion and 37 T to G transversion into the Spi-B binding site. In all patients, a prevalence of genotypes 1A and 1B, the predominant JCPyV genotypes in Europe, was observed.
It has been important to understand whether the specific inflammatory scenario in different immune-mediated diseases could affect JCPyV reactivation from latency, in particular from kidneys. Moreover, for a more accurate PML risk stratification, testing JC viruria seems to be useful to identify patients who harbor JCPyV but with an undetectable JCPyV-specific humoral immune response. In these patients, it may also be important to study the JCPyV NCCR rearrangement: in particular, Spi-B expression in PBMCs could play a crucial role in JCPyV replication and NCCR rearrangement.
在生物治疗期间，免疫介导疾病患者中由多瘤病毒 JC（JCPyV）引起的进行性多灶性白质脑病（PML）发病引发了对这些药物安全性的担忧。因此，本研究的目的是监测不同免疫介导疾病且接受生物制剂治疗的患者中 JCPyV 的再激活情况，并分析其非编码控制区（NCCR）和病毒蛋白 1（VP1）。
我们对招募时（t0）及之后每 4 个月（t1、t2、t3、t4）采集的生物样本进行 JCPyV 特异性定量 PCR。随后，对 NCCR 和 VP1 进行重排分析。数据采用 χ2 检验进行分析。
结果显示，在 t0 时，慢性炎症性风湿性疾病患者尿液中的 JCPyV 载量显著高于多发性硬化症（MS）和克罗恩病（CD）患者（p≤0.05）。在 MS 患者中，使用那他珠单抗 1 年后，JC 病毒尿症与 JCPyV 抗体之间也存在显著关联（p = 0.04）。最后，NCCR 分析表明所有尿液样本中均存在原型样序列，而在接受英夫利昔单抗治疗 16 个月后从 2 例 CD 患者的结肠直肠活检组织中发现了重排的 NCCR IR 型。此外，从 2 例在 t0 和 t3 时具有 JCPyV 抗体的 MS 患者外周血单个核细胞（PBMC）中分离出的序列显示为 NCCR IIR 型，有一个 98 bp 单位的重复和一个 66 bp 的插入，导致 boxB 缺失以及 Spi - B 结合位点处有 37 个 T 到 G 的颠换。在所有患者中，均观察到欧洲主要的 JCPyV 基因型 1A 和 1B 的流行。
了解不同免疫介导疾病中的特定炎症情况是否会影响 JCPyV 从潜伏状态重新激活，尤其是从肾脏重新激活，具有重要意义。此外，为了更准确地进行 PML 风险分层，检测 JC 病毒尿症似乎有助于识别携带 JCPyV 但 JCPyV 特异性体液免疫反应无法检测到的患者。在这些患者中，研究 JCPyV NCCR 重排也可能很重要：特别是，PBMC 中的 Spi - B 表达可能在 JCPyV 复制和 NCCR 重排中起关键作用。
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