Antiviral Therapy for Polyomavirus Infection

多瘤病毒感染的抗病毒治疗

基本信息

批准号：
7233933
负责人：
Aron Eliot Lukacher
金额：
$ 19.13万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-15 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7233933
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Actins Acute Address Adolescence Affect Antibodies Antigens Antiviral Agents Antiviral Therapy Applications Grants CD8B1 gene Cell Communication Cell Survival Cells Chronic Chronic Myeloid Leukemia Clinical Treatment Clonal Deletion Depressed mood Elderly Family Fluorescence Microscopy Generations Gleevec Graft Rejection Human Immigration Immunity Immunologic Monitoring Immunology Immunosuppressive Agents In Vitro Individual Infection Integrin alpha4beta1 Investigation Kidney Transplantation Lymphocyte Maintenance Malignant Neoplasms Mediating Memory Microtubules Modality Modeling Multiple Sclerosis Mus Neuraxis Pathogenesis Patients Pharmaceutical Preparations Philadelphia Chromosome Phosphotransferases Polyoma Virus Middle T Staining Method Polyomavirus Polyomavirus Infections Population Progressive Multifocal Leukoencephalopathy Protein Tyrosine Kinase Range Relapse Risk Role System T memory cell T-Lymphocyte Testing Therapeutic Therapeutic Uses Transplant Recipients Treatment Protocols Tyrosine Kinase Inhibitor Tysabri Viral Viral Load result Virion Virus Virus Diseases Virus Inhibitors Virus Replication ataxia telangiectasia mutated protein base cell motility central nervous system demyelinating disorder design immune function immunosuppressed improved in vivo inhibitor/antagonist kinase inhibitor mouse polyomavirus novel novel therapeutics pathogen prevent response src-Family Kinases trafficking uptake virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Polyomaviruses are ubiquitous silent pathogens in a variety of vertebrate hosts, including humans, but become opportunistic pathogens in the setting of depressed immune function. By early adolescence, nearly all humans are infected by both of the two known polyomaviruses, BKV and JCV. Reactivation of BKV is a leading cause of kidney transplant rejection and, in the elderly and AIDS patients, JCV reactivation causes the progressive fatal central nervous system (CNS) demyelinating disease called Progressive Multifocal Leukoencephalopathy (PML). PML also occurs in conjunction with immunosuppressant drug regimens. Recently, several patients treated with Tysabri, a humanized VLA-4 antibody that controls relapses in multiple sclerosis patients by restricting T cell immigration to the CNS, developed PML. There is currently no clinically effective antiviral therapy for polyomavirus infection, or the consequences of reactivation. Repetitive antigen encounter during persistent infection causes functional debilitation of virus-specific T cells, with clonal deletion the eventual consequence of chronic TCR engagement. The duration and magnitude of persistent viral infection govern the survival of memory T cells and their ability to limit viral replication. Thus, therapeutics that lower viral load will promote generation of effective antiviral T cell memory. Because of the narrow host range of this virus family, the mouse-polyoma virus (PyV) system provides the only tractable model to evaluate pathogenesis of and immunity to this clinically important virus family, and to develop and test novel therapeutic compounds. We recently found that Abl-family tyrosine kinases are required for replication of PyV and that inhibitors of these kinases (e.g. Novartis' Gleevec), rationally designed to control specific human cancers (e.g., Philadelphia chromosome+ chronic myelogenous leukemia), block PyV replication both in vitro and in mice. In this exploratory application application, we have combined the expertise of the Drs. Aron Lukacher (mouse polyoma virus pathogenesis and viral immunology) and Daniel Kalman (tyrosine kinases, Abl-family inhibitory compounds, virion-host cell interaction, deconvolution fluorescence microscopy) to investigate mechanism(s) of inhibition by these compounds in vitro and their capacity to limit PyV infection in vivo. In Specific Aim 1, we will test the hypothesis that Abl-family tyrosine kinases are involved in early steps in PyV cell uptake and intracellular trafficking and in replication. Because of the importance of CD8 T cells in immunosurveillance for polyomavirus-infected cells, and the detrimental effect of persistent viral infections on memory T cell survival and function, we further hypothesize that reductions in viral load mediated by the Abl-family kinase inhibitors will improve memory polyomavirus-specific CD8 T cell responses and further curtail polyomavirus reactivation (Specific Aim 2). Investigation of the mechanism of inhibition by these compounds and their capacity to limit PyV infection in vivo will provide proof-of-principle for their therapeutic use to counter polyomavirus reactivation in high-risk populations. Project Narrative: Nearly all individuals are infected lifelong by two human polyomaviruses, otherwise silent infections that have debilitating, potentially fatal, consequences in immunosuppressed individuals (e.g., kidney transplant recipients, HIV/AIDS). There is no effective antiviral therapy for polyomavirus infection. In this application, studies are proposed to explore the mechanism for the novel observation that compounds that inhibit Abl- family tyrosine kinases (e.g., FDA-approved Gleevec) limit polyomavirus infection, a critical prelude for their potential therapeutic use to prevent polyomavirus reactivation in immunosuppressed individuals.

描述（由申请人提供）：多瘤病毒是包括人类在内的各种脊椎动物宿主中普遍存在的无声病原体，但在免疫功能抑郁症的情况下成为机会性病原体。到青春期早期，几乎所有人类都被两个已知的多瘤病毒BKV和JCV感染。 BKV的重新激活是肾脏移植排斥反应的主要原因，在老年人和AIDS患者中，JCV重新激活导致进行性致命中枢神经系统（CNS）脱髓鞘疾病，称为进行性多焦点白细胞症（PML）。 PML还与免疫抑制剂药物方案一起发生。最近，几名用tysabri治疗的患者是一种人源化的VLA-4抗体，可通过将T细胞移民限制为中枢神经系统，从而控制多发性硬化症患者的复发。目前尚无用于多瘤病毒感染的临床有效抗病毒疗法，也没有重新激活的后果。持续感染期间的重复抗原遇到会导致病毒特异性T细胞的功能衰弱，克隆缺失最终导致慢性TCR参与的结果。持续性病毒感染的持续时间和幅度控制着记忆T细胞的存活及其限制病毒复制的能力。因此，较低病毒载量的治疗剂将促进有效的抗病毒药性T细胞记忆的产生。由于该病毒家族的宿主范围狭窄，小鼠 - 多层病毒（PYV）系统提供了唯一可评估对该临床重要病毒家族发病机理和免疫力的可拖动模型，并开发和测试新型的治疗化合物。我们最近发现，复制PYV所必需的ABL家族酪氨酸激酶，并且这些激酶的抑制剂（例如诺华Gleevec）抑制了用于控制特定的人类癌症（例如Philadelphia染色体+慢性髓质白血病）的理性设计，block pyv pyv均已重复和vittro和Vitro insice insice insice insice insice insice insice。在此探索性应用程序中，我们结合了DRS的专业知识。 Aron Lukacher（小鼠多瘤病毒发病机理和病毒免疫学）和Daniel Kalman（酪氨酸激酶，ABL - 家庭抑制性化合物，Virion-Host细胞相互作用，反向透射荧光显微镜），以研究这些化合物在玻璃体中的抑制作用和限制PYV Infection vivo的能力。在特定目标1中，我们将检验以下假设：ABL家庭酪氨酸激酶参与PYV细胞摄取和细胞内贩运和复制的早期步骤。由于CD8 T细胞在免疫监视性中的重要性对多瘤病毒感染细胞的重要性，以及持续病毒感染对记忆T细胞存活和功能的有害作用，我们进一步假设由ABL - 家庭抑制剂介导的病毒负荷介导的减少病毒载量会改善记忆性cD8的反应（进一步）。研究这些化合物抑制机制及其在体内限制PYV感染的能力将提供原则证明其治疗用途，以抵抗高风险群体中的多瘤病毒重新激活。项目叙述：几乎所有个体都被两种人类多瘤病毒感染，否则沉默的感染具有使免疫抑制个体（例如肾脏移植受者HIV/AIDS）具有令人衰弱的，潜在致命的后果。没有有效的抗病毒治疗多瘤病毒感染。在此应用中，提出了研究来探索新型观察的机制，该新观察结果抑制了抑制ABL-家族酪氨酸激酶（例如FDA批准的Gleevec）限制多瘤病毒感染，这是其潜在治疗用途的关键序曲，以防止在免疫抑制的个体中进行多瘤病毒的潜在治疗。