Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.
mBio. 2013 Nov 12;4(6):e00729-13. doi: 10.1128/mBio.00729-13.
Polyomaviruses are ubiquitous pathogens that cause severe disease in immunocompromised individuals. JC polyomavirus (JCPyV) is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), whereas BK polyomavirus (BKPyV) causes polyomavirus-induced nephropathy and hemorrhagic cystitis. Vaccines or antiviral therapies targeting these viruses do not exist, and treatments focus on reducing the underlying causes of immunosuppression. We demonstrate that retro-2(cycl), an inhibitor of ricin and Shiga-like toxins (SLTs), inhibits infection by JCPyV, BKPyV, and simian virus 40. Retro-2(cycl) inhibits retrograde transport of polyomaviruses to the endoplasmic reticulum, a step necessary for productive infection. Retro-2(cycl) likely inhibits polyomaviruses in a way similar to its ricin and SLT inhibition, suggesting an overlap in the cellular host factors used by bacterial toxins and polyomaviruses. This work establishes retro-2(cycl) as a potential antiviral therapy that broadly inhibits polyomaviruses and possibly other pathogens that use retrograde trafficking.
The human polyomaviruses JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) cause rare but severe diseases in individuals with reduced immune function. During immunosuppression, JCPyV disseminates from the kidney to the central nervous system and destroys oligodendrocytes, resulting in the fatal disease progressive multifocal leukoencephalopathy. Kidney transplant recipients are at increased risk of BKPyV-induced nephropathy, which results in kidney necrosis and loss of the transplanted organ. There are currently no effective therapies for JCPyV and BKPyV. We show that a small molecule named retro-2(cycl) protects cells from infection with JCPyV and BKPyV by inhibiting intracellular viral transport. Retro-2(cycl) treatment reduces viral spreading in already established infections and may therefore be able to control infection in affected patients. Further optimization of retro-2(cycl) may result in the development of an effective antiviral therapy directed toward pathogens that use retrograde trafficking to infect their hosts.
多瘤病毒是普遍存在的病原体，可导致免疫功能低下的个体发生严重疾病。JC 多瘤病毒（JCPyV）是致命脱髓鞘疾病进行性多灶性白质脑病（PML）的病原体，而 BK 多瘤病毒（BKPyV）可引起多瘤病毒诱导的肾病和出血性膀胱炎。针对这些病毒的疫苗或抗病毒疗法尚不存在，治疗方法侧重于减少免疫抑制的根本原因。我们证明， ricin 和类志贺毒素（SLTs）的抑制剂 retro-2（cycl）可抑制 JCPyV、BKPyV 和猿猴病毒 40 的感染。 Retro-2（cycl）抑制多瘤病毒向内质网的逆行转运，这是产生活性感染所必需的步骤。 Retro-2（cycl）可能以类似于其 ricin 和 SLT 抑制的方式抑制多瘤病毒，这表明细菌毒素和多瘤病毒使用的细胞宿主因子存在重叠。这项工作确立了 retro-2（cycl）作为一种潜在的抗病毒疗法，可广泛抑制多瘤病毒和可能使用逆行运输的其他病原体。
人类多瘤病毒 JC 多瘤病毒（JCPyV）和 BK 多瘤病毒（BKPyV）可在免疫功能低下的个体中引起罕见但严重的疾病。在免疫抑制期间，JCPyV 从肾脏传播到中枢神经系统并破坏少突胶质细胞，导致致命的疾病进行性多灶性白质脑病。肾移植受者患 BKPyV 诱导的肾病的风险增加，这会导致肾脏坏死和移植器官丧失。目前尚无针对 JCPyV 和 BKPyV 的有效疗法。我们表明，一种名为 retro-2（cycl）的小分子通过抑制细胞内病毒转运来保护细胞免受 JCPyV 和 BKPyV 的感染。 Retro-2（cycl）治疗可减少已建立的感染中的病毒扩散，因此可能能够控制受感染患者的感染。 retro-2（cycl）的进一步优化可能会导致针对使用逆行运输感染宿主的病原体的有效抗病毒疗法的发展。
