From the Department of Neurology (F.S., S.L., G.R.F., C.W.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany; Experimental Immunotherapeutics Unit (I.C.), NIH, Bethesda, MD; Cognitive Neuroscience (G.R.F.), Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich; Institute of Virology (S.S.), National Reference Center for Papilloma- and Polyomaviruses, Faculty of Medicine, University Hospital Cologne; Department of Neurology (T.S.), Hannover Medical School; Institute of Neuropathology (I.M.), University Medical Center Göttingen; and Department of Neuroradiology (M.P.W.), Hannover Medical School, Germany.
Neurology. 2023 Oct 17;101(16):700-713. doi: 10.1212/WNL.0000000000207622. Epub 2023 Jul 24.
JC polyomavirus (JCV) establishes an asymptomatic latent and/or persistent infection in most of the adult population. However, in immunocompromised individuals, JCV can cause a symptomatic infection of the brain, foremost progressive multifocal leukoencephalopathy (PML). In the past 2 decades, there has been increasing concern among patients and the medical community because PML was observed as an adverse event in individuals treated with modern (selective) immune suppressive treatments for various immune-mediated diseases, especially multiple sclerosis. It became evident that this devastating complication also needs to be considered beyond the patient populations historically at risk, including those with hematologic malignancies or HIV-infected individuals. We review the clinical presentation of PML, its variants, pathogenesis, and current diagnostic approaches. We further discuss the need to validate JCV-directed interventions and highlight current management strategies based on early diagnosis and restoring JCV-specific cellular immunity, which is crucial for viral clearance and survival. Finally, we discuss the importance of biomarkers for diagnosis and response to therapy, instrumental in defining sensitive study end points for successful clinical trials of curative or preventive therapeutics. Advances in understanding PML pathophysiology, host and viral genetics, and diagnostics in conjunction with novel immunotherapeutic approaches indicate that the time is right to design and perform definitive trials to develop preventive options and curative therapy for JCV-associated diseases.
JC 多瘤病毒（JCV）在大多数成年人群中建立无症状的潜伏和/或持续性感染。然而，在免疫功能低下的个体中，JCV 可引起脑部的症状性感染，主要是进行性多灶性白质脑病（PML）。在过去的 20 年中，患者和医学界越来越关注 PML，因为在接受现代（选择性）免疫抑制治疗各种免疫介导性疾病的个体中观察到 PML 作为不良事件，特别是多发性硬化症。显然，除了历史上处于危险中的患者人群（包括患有血液恶性肿瘤或 HIV 感染的个体）之外，还需要考虑这种破坏性并发症。我们回顾了 PML 的临床表现、其变体、发病机制和当前的诊断方法。我们进一步讨论了验证针对 JCV 的干预措施的必要性，并根据早期诊断和恢复针对 JCV 的细胞免疫强调了当前的管理策略，这对于病毒清除和生存至关重要。最后，我们讨论了诊断和治疗反应的生物标志物的重要性，这些标志物对于成功进行治疗或预防性治疗的临床试验确定敏感的研究终点具有重要意义。对 PML 病理生理学、宿主和病毒遗传学以及诊断的理解的进展以及新型免疫治疗方法的进展表明，现在正是设计和进行明确试验以开发针对 JCV 相关疾病的预防选择和治疗性疗法的合适时机。
