Antiviral treatment of BK polyomavirus reactivation

BK 多瘤病毒再激活的抗病毒治疗

基本信息

批准号：
10730924
负责人：
Sunnie R Thompson
金额：
$ 22.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730924
关键词：
ATR gene Acute Affect Aftercare Allografting Antiviral Agents BK Virus Bladder Bone Marrow Transplantation Bortezomib Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cell Nucleus Cell Survival Cells Childhood Clinical Clinical Research Clinical Trials Cystitis DNA Damage DNA Viruses Data Dose Drug toxicity Epithelial Cells FDA approved Failure Foundations Generations Goals Graft Rejection Hemorrhage Human Immune system Immunosuppression Infection Injury Kidney Kidney Diseases Kidney Transplantation Large T Antigen Mitosis Monitor Morbidity - disease rate Nonstructural Protein Oral Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacological Treatment Phosphotransferases Plasma Polyomavirus Polyomavirus Infections Polyploid Cells Population Probability Production Productivity Proteasome Inhibition Proteasome Inhibitor Risk S phase Small T Antigen Stem cell transplant Structural Protein Symptoms Testing Toxic effect Transplant Recipients Tubular formation Urine Viral Viral Genome Viremia Virus Virus Assembly Virus Replication Virus Shedding ataxia telangiectasia mutated protein cell type clinically relevant early phase clinical trial experience fitness immunosuppressed inhibitor kidney cell mortality multicatalytic endopeptidase complex prevent protein degradation response transcriptome sequencing transcriptomics viral DNA

项目摘要

Project Summary BK polyomavirus (BKPyV) associated nephropathy (PVAN) is the leading cause of kidney transplant loss (~10%/year). BKPyV infects approximately 80-90% of people during childhood and is kept in check by the host immune system. However, in transplant patients BKPyV reactivation causes PVAN due to suppression of their immune system. The current treatment is reduction of immunosuppression, which increases the risk of graft rejection, but untreated PVAN will result in allograft loss. Patients are routinely monitored for BKPyV in the urine and the plasma, providing an opportunity to treat early with antivirals, before decreasing immunosuppression is required. Based on our mechanistic studies, we have identified two host pathways required for BKPyV production in primary kidney cells that, when inhibited by existing drugs, reduce viral titers. We discovered that bortezomib, a proteasome inhibitor, potently decreases viral titers by 3 logs, at low doses and without affecting cell fitness. We will also test newer generation proteasome inhibitors that are less toxic and/or orally available, carfilzomib and ixazomib. Given that the proteasome is required early during infection, we sought to inhibit a second host target that would reduce viral production late in infection, or could potentially eliminate virally infected cells. BKPyV requires activation of the DNA damage response (DDR) for cell cycle arrest, to prolong S phase for viral replication and assembly. Inhibiting the DDR activating kinases (ATM and ATR), forces BKPyV infected, but not mock infected, cells exit S phase, and viral titers are reduced. Our studies revealed two potent targets, the proteasome and the DDR, which both have known inhibitors, one is already FDA approved, and the other is in clinical trials (both are being used for other indications). The proposed aims will determine the effects of these inhibitors, and combinations of them, on viral titers, cell viability and cell cycle regulation, using clinical viral isolates to infect primary renal proximal tubular epithelial cells, which are the natural cell type infected in humans. We will sequence the virus before and after inhibition studies to determine if there are changes to the viral genome. This proof-of-concept data is required in order to test the inhibitor(s) in clinical trials (beyond the scope of this study) as antivirals that can protect against graft loss caused by BKPyV reactivation. There is an urgent need for antivirals that can either prevent or treat BKPyV reactivation prior to or in conjunction with immunosuppression.

项目概要 BK 多瘤病毒 (BKPyV) 相关肾病 (PVAN) 是肾移植的主要原因损失（~10%/年）。 BKPyV 在儿童时期感染大约 80-90% 的人，并且受到以下因素的控制：宿主免疫系统。然而，在移植患者中，BKPyV 重新激活会导致 PVAN，因为抑制他们的免疫系统。目前的治疗方法是减少免疫抑制，增加移植物排斥的风险，但未经治疗的 PVAN 将导致同种异体移植物丢失。患者通常会监测尿液和血浆中的 BKPyV，提供早期使用抗病毒药物治疗的机会，在需要减少免疫抑制之前。根据我们的机制研究，我们已经确定原代肾细胞中 BKPyV 产生所需的两条宿主途径，当被现有的抑制时药物，降低病毒滴度。我们发现硼替佐米（一种蛋白酶体抑制剂）可有效降低病毒滴度 3 个对数，低剂量且不影响细胞健康。我们还将测试新一代蛋白酶体抑制剂卡非佐米和伊沙佐米毒性较小和/或口服。鉴于感染早期需要蛋白酶体，我们试图抑制第二个宿主目标将减少感染后期的病毒产生，或者可能消除病毒感染的细胞。 BKPyV 需要激活 DNA 损伤反应 (DDR) 来实现细胞周期停滞，从而延长 S 期病毒复制和组装。抑制 DDR 激活激酶（ATM 和 ATR），强制 BKPyV 感染，但未模拟感染，细胞退出S期，病毒滴度降低。我们的研究揭示了两个有效的靶点：蛋白酶体和 DDR，这两个靶点均已为人所知抑制剂，一种已经获得 FDA 批准，另一种正在临床试验中（两者都被用于其他指示）。拟议的目标将确定这些抑制剂及其组合对病毒滴度、细胞活力和细胞周期调节，使用临床病毒分离株感染原发性肾近端肾小管上皮细胞，是人类感染的自然细胞类型。我们先对病毒进行测序并进行抑制研究以确定病毒基因组是否发生变化。这个概念验证数据需要在临床试验（超出本研究的范围）中测试抑制剂作为抗病毒药物可以防止 BKPyV 重新激活引起的移植物损失。目前迫切需要抗病毒药物在免疫抑制之前或与免疫抑制同时预防或治疗 BKPyV 重新激活。