Data Sheet 1_BK polyomavirus-associated progressive multifocal leukoencephalopathy following mogamulizumab therapy for erythrodermic mycosis fungoides.pdf

IntroductionBK polyomavirus (BKPyV) is a ubiquitous human pathogen that typically causes nephropathy and hemorrhagic cystitis in immunocompromised patients. Although BKPyV shares close genetic and structural similarity with JC polyomavirus (JCPyV), which is responsible for progressive multifocal leukoencephalopathy (PML), its neurotropic potential remains poorly characterized. Rare reports have suggested possible central nervous system (CNS) involvement under conditions of severe immune suppression. Here, we describe the first documented case of BKPyV-associated PML in a patient with erythrodermic mycosis fungoides treated with Mogamulizumab, a CCR4-targeting monoclonal antibody that profoundly alters immune surveillance.
ResultsWe describe a patient with erythrodermic mycosis fungoides and long-standing immunological frailty, who developed neurological symptoms during Mogamulizumab therapy. Brain MRI showed multifocal white matter lesions compatible with PML. BKPyV DNA was detected in plasma, urine, and cerebrospinal fluid (CSF), while JCPyV DNA was absent. Serological testing showed high anti-BKPyV and anti-JCPyV IgG levels in plasma, indicating prior exposure to both viruses, while antibodies were undetectable in CSF, consistent with lack of intrathecal synthesis. This compartmental dissociation between plasma and CSF, together with the detection of BKPyV DNA and the absence of JCPyV DNA in CSF, supports BKPyV as the etiological neurotropic agent responsible for leukoencephalopathy. Sequencing of the VP1 and NCCR regions revealed compartment-specific nucleotide and amino acid variants, including non-conservative substitutions in the CSF isolate, suggesting intra-host viral heterogeneity. Compartment-specific sequence variability of viral protein 1 (VP1) and structural rearrangements of the non-coding control region (NCCR), particularly the loss of the Q and R block in CSF-derived isolates, underscore intra-host heterogeneity of BKV and may contribute to its adaptation and neurotropic potential.
ConclusionThis is the first documented case of BKPyV-associated PML in a Mogamulizumab-treated patient. These findings highlight intra-host heterogeneity at the protein level, possibly reflecting compartment-specific viral evolution, and underscore the need for vigilant BKPyV and JCPyV monitoring during Mogamulizumab treatment.

引言
BK多瘤病毒（BK polyomavirus, BKPyV）是一种广泛分布的人类病原体，通常可在免疫功能低下患者中引发肾病与出血性膀胱炎。尽管BKPyV与导致进行性多灶性白质脑病（progressive multifocal leukoencephalopathy, PML）的JC多瘤病毒（JC polyomavirus, JCPyV）在遗传与结构层面具有高度相似性，但其嗜神经潜能仍未得到充分阐明。既往已有罕见病例报道提示，在严重免疫抑制状态下，BKPyV可能累及中枢神经系统（central nervous system, CNS）。本研究报道首例接受莫加珠单抗（Mogamulizumab，一种靶向CCR4的单克隆抗体，可显著改变免疫监视功能）治疗的红皮病样蕈样肉芽肿患者发生BKPyV相关PML的病例。

结果
本研究报道1例合并长期免疫功能低下的红皮病样蕈样肉芽肿患者，在接受莫加珠单抗治疗期间出现神经系统症状。脑部磁共振成像（magnetic resonance imaging, MRI）显示多灶性白质病变，符合PML的影像学特征。在患者血浆、尿液与脑脊液（cerebrospinal fluid, CSF）中均检测到BKPyV DNA，而未检出JCPyV DNA。血清学检测结果显示，血浆中抗BKPyV与抗JCPyV IgG抗体水平较高，提示患者既往曾暴露于这两种病毒；但脑脊液中未检测到相关抗体，符合鞘内合成缺失的表现。血浆与脑脊液之间的这种分区解离现象，结合脑脊液中检出BKPyV DNA且未检出JCPyV DNA的结果，支持BKPyV为导致该白质脑病的嗜神经致病因子。对VP1与非编码调控区（NCCR）的测序结果显示，存在分区特异性的核苷酸与氨基酸变异，包括脑脊液分离株中的非保守替换，提示存在宿主内病毒异质性。病毒衣壳蛋白1（VP1）的分区特异性序列变异与非编码调控区（NCCR）的结构重排——尤其是脑脊液来源分离株中Q与R区段的缺失——进一步凸显了BKPyV的宿主内异质性，或有助于其适应性进化与嗜神经潜能的获得。

结论
本研究为首例接受莫加珠单抗治疗的患者发生BKPyV相关PML的正式报道。本研究结果揭示了宿主内蛋白质水平的异质性，可能反映了病毒的分区特异性进化，并强调在莫加珠单抗治疗期间需对BKPyV与JCPyV进行密切监测。