多瘤病毒是物种特异性DNA病毒,可在免疫受损的个体中引起疾病。尽管它们是几种疾病的病原体,目前还没有批准用于治疗多瘤病毒感染的抗病毒药物.Brincidofovir(BCV)是一种被批准用于治疗痘病毒感染的抗病毒药物,并已显示出对其他双链DNA病毒的活性。在这项研究中,我们使用小鼠多瘤病毒(MuPyV)在体外和体内测试了BCV对多瘤病毒感染的功效。BCV抑制原代小鼠肾细胞和大脑皮层细胞中的病毒产生。用MuPyV基因组DNA转染的细胞的BCV处理导致病毒水平降低,表明病毒抑制发生在进入后。尽管体外BCV处理对病毒DNA和RNA水平的影响有限,药物治疗与病毒蛋白的减少有关,提高BCV在转录后起作用以抑制MuPyV感染的可能性。在老鼠身上,BCV治疗耐受性良好,和预防性治疗导致病毒DNA水平降低,并有效抑制肾脏和大脑中感染性病毒的产生。在患有慢性多瘤病毒感染的小鼠中,BCV的治疗性给药减少了病毒血症并减少了肾脏的感染。这些数据表明,BCV在体内发挥抗多瘤病毒感染的抗病毒活性,支持使用BCV治疗临床多瘤病毒感染的进一步研究。
目的:在人群中广泛存在,并且能够在个体的一生中渐近地持续存在,多瘤病毒感染会在免疫功能低下的人群中造成巨大的疾病负担。经历免疫抑制的个体,例如肾移植患者或接受自身免疫性疾病治疗的患者,尤其是多瘤病毒相关疾病的高风险。因为不存在用于治疗多瘤病毒感染的抗病毒药物,多瘤病毒相关疾病的治疗通常包括减少或停止免疫调节治疗.由于移植排斥的风险和不良免疫反应的潜在发展,这可能是危险的。因此,迫切需要开发靶向多瘤病毒的抗病毒药物。这里,我们研究了Brindofovir的作用,FDA批准的抗病毒药物,使用小鼠多瘤病毒在体内感染多瘤病毒。我们证明这种药物在小鼠中具有良好的耐受性,降低感染性病毒滴度,并限制病毒病理学,这表明Brindofovir作为抗多瘤病毒治疗的潜力。
Polyomaviruses are species-specific DNA viruses that can cause disease in immunocompromised individuals. Despite their role as the causative agents for several diseases, there are no currently approved antivirals for treating polyomavirus infection. Brincidofovir (BCV) is an antiviral approved for the treatment of poxvirus infections and has shown activity against other double-stranded DNA viruses. In this study, we tested the efficacy of BCV against
polyomavirus infection in vitro and in vivo using mouse
polyomavirus (MuPyV). BCV inhibited virus production in primary mouse kidney cells and brain cortical cells. BCV treatment of cells transfected with MuPyV genomic DNA resulted in a reduction in virus levels, indicating that viral inhibition occurs post-entry. Although in vitro BCV treatment had a limited effect on viral DNA and RNA levels, drug treatment was associated with a reduction in viral protein, raising the possibility that BCV acts post-transcriptionally to inhibit MuPyV infection. In mice, BCV treatment was well tolerated, and prophylactic treatment resulted in a reduction in viral DNA levels and a potent suppression of infectious virus production in the kidney and brain. In mice with chronic polyomavirus infection, therapeutic administration of BCV decreased viremia and reduced infection in the kidney. These data demonstrate that BCV exerts antiviral activity against polyomavirus infection in vivo, supporting further investigation into the use of BCV to treat clinical
polyomavirus infections.
OBJECTIVE: Widespread in the human population and able to persist asymptomatically for the life of an individual, polyomavirus infections cause a significant disease burden in the immunocompromised. Individuals undergoing immune suppression, such as kidney transplant patients or those treated for autoimmune diseases, are particularly at high risk for polyomavirus-associated diseases. Because no antiviral agent exists for treating
polyomavirus infections, management of
polyomavirus-associated diseases typically involves reducing or discontinuing immunomodulatory therapy. This can be perilous due to the risk of transplant rejection and the potential development of adverse immune reactions. Thus, there is a pressing need for the development of antivirals targeting polyomaviruses. Here, we investigate the effects of brincidofovir, an FDA-approved antiviral, on polyomavirus infection in vivo using mouse
polyomavirus. We show that the drug is well-tolerated in mice, reduces infectious viral titers, and limits viral pathology, indicating the potential of brincidofovir as an anti-polyomavirus therapeutic.