Antiviral Therapy for Polyomavirus Infection

多瘤病毒感染的抗病毒治疗

• 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
• 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

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多种脊椎动物宿主中普遍存在的沉默病原体，但在免疫功能低下的情况下成为机会性病原体。到青春期早期，几乎所有人类都会感染两种已知的多瘤病毒：BKV 和 JCV。 BKV 重新激活是肾移植排斥的主要原因，在老年人和艾滋病患者中，JCV 重新激活会导致进行性致命的中枢神经系统 (CNS) 脱髓鞘疾病，称为进行性多灶性白质脑病 (PML)。 PML 也与免疫抑制剂药物治疗同时发生。最近，几位接受 Tysabri（一种人源化 VLA-4 抗体，通过限制 T 细胞迁移到 CNS 来控制多发性硬化症患者复发）治疗的患者出现了 PML。目前临床上尚无针对多瘤病毒感染或重新激活后果的有效抗病毒疗法。持续感染期间重复的抗原遭遇会导致病毒特异性 T 细胞功能衰弱，克隆缺失是长期 TCR 参与的最终结果。持续病毒感染的持续时间和程度决定着记忆 T 细胞的存活及其限制病毒复制的能力。因此，降低病毒载量的疗法将促进有效抗病毒T细胞记忆的产生。由于该病毒家族的宿主范围较窄，小鼠多瘤病毒（PyV）系统提供了唯一易于处理的模型来评估该临床重要病毒家族的发病机制和免疫性，以及开发和测试新型治疗化合物。我们最近发现，Abl 家族酪氨酸激酶是 PyV 复制所必需的，并且这些激酶的抑制剂（例如诺华的格列卫）经过合理设计以控制特定人类癌症（例如费城染色体+慢性粒细胞性白血病），可在以下两种情况下阻断 PyV 复制：体外和小鼠体内。在这个探索性应用中，我们结合了博士的专业知识。 Aron Lukacher（小鼠多瘤病毒发病机制和病毒免疫学）和 Daniel Kalman（酪氨酸激酶、Abl 家族抑制化合物、病毒体-宿主细胞相互作用、解卷积荧光显微镜）研究这些化合物的体外抑制机制及其能力以限制体内 PyV 感染。在具体目标 1 中，我们将检验以下假设：Abl 家族酪氨酸激酶参与 PyV 细胞摄取、细胞内运输和复制的早期步骤。由于 CD8 T 细胞在多瘤病毒感染细胞的免疫监视中的重要性，以及持续病毒感染对记忆 T 细胞存活和功能的不利影响，我们进一步假设 Abl 家族激酶抑制剂介导的病毒载量减少将改善记忆多瘤病毒特异性 CD8 T 细胞反应并进一步减少多瘤病毒再激活（具体目标 2）。对这些化合物的抑制机制及其限制体内 PyV 感染的能力的研究将为它们在高危人群中对抗多瘤病毒重新激活的治疗用途提供原理证明。项目叙述：几乎所有的人都会终生感染两种人类多瘤病毒，否则这种感染是无声的，会对免疫抑制的个体（例如肾移植受者、艾滋病毒/艾滋病）造成衰弱甚至可能致命的后果。对于多瘤病毒感染没有有效的抗病毒治疗。在本申请中，建议研究探索抑制 Abl 家族酪氨酸激酶的化合物（例如 FDA 批准的格列卫）限制多瘤病毒感染的新观察机制，这是其潜在治疗用途的关键前奏，以防止免疫抑制的多瘤病毒重新激活。个人。