Can persistent gamma-herpesviruses be purged from the host?

持久性伽马疱疹病毒可以从宿主体内清除吗？

基本信息

批准号：
7677077
负责人：
Marcia A Blackman
金额：
$ 26.7万
依托单位：
TRUDEAU INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-19 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7677077
关键词：
Address Aftercare Animals Antibodies Antibody Therapy Antiviral Agents B-Cell Development B-Cell Lymphomas B-Lymphocyte Subsets B-Lymphocytes Cell Therapy Clinic Clinical Data Dendritic Cells Development Epstein-Barr Virus Infections Event Experimental Animal Model HIV Herpesviridae Herpesviridae Infections Human Human Herpesvirus 4 Human Herpesvirus 8 Immune system Immunity Immunocompetent Immunosuppression Infection Injection of therapeutic agent Laboratory mice Latent Virus Life Life Cycle Stages Lymphoproliferative Disorders Lytic Phase Maintenance Malignant Neoplasms Memory B-Lymphocyte Methods Modeling Monitor Mus Myelogenous Oncogenic Viruses Pharmaceutical Preparations Pharmacotherapy Population Role Testing Therapeutic Translating Transplantation Viral Virus Virus Latency cell type gammaherpesvirus high risk in vivo in vivo Model infected vector rodent macrophage man memory CD4 T lymphocyte mouse model mutant prophylactic prospective public health relevance purge research study rituximab success therapeutic development therapeutic vaccine therapy design tool

项目摘要

DESCRIPTION (provided by applicant): The human gamma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), establish persistent infections that are associated with the development of a variety of malignancies. Whereas the lytic phase of the infection is controlled by the immune system, the viruses evade immunity by establishing life-long latency, even in an immunocompetent host. Pathological consequences of infection are primarily associated with viral latency, and no prophylactic or therapeutic vaccines are available. B cells are the major reservoir of latent virus, and one important clinical problem associated with EBV infection is the development of B cell lymphoproliferative disease and/or B cell lymphomas following post-transplant immunosuppression. Promising results with the clinical use of Rituximab (anti-B cell antibody therapy) to target EBV-transformed B cells in post-transplant malignancies suggest the possibility that anti-B cell therapy could be used prophylactically to substantially lower latent load or even to purge latency from the host prior to transplantation. In order to test this and other therapeutic approaches, it is essential to understand mechanisms involved in maintenance of long-term latency, which can best be elucidated in an experimental animal model. Gamma HV68 (also referred to as MHV-68) is a naturally occurring gamma-herpesvirus of rodents that infects the laboratory mouse, providing an easily manipulated small animal natural infection model for performing experiments not possible in man. The current proposal exploits the mouse model to address mechanisms underlying the maintenance of latency. Importantly, we will test the hypothesis that latent virus can be purged from an infected host. In Aim 1, we will determine whether viral reactivation and re-infection contribute to the maintenance of long-term latency in B cells, macrophages and dendritic cells. In Aim 2 we will determine whether treatment with B cell depleting antibodies to mimic Rituximab therapy, with or without anti-viral drugs, can reduce or eliminate long-term latency. PUBLIC HEALTH RELEVANCE: The gamma-herpesviruses are oncogenic viruses that are widely disseminated in the human population and associated with the development of malignancies. Analysis of the well-developed mouse model of gamma- herpesvirus infection provides an important tool to dissect fundamental events in the reactivation of viral latency, and serves as an in vivo model for testing proof of concept therapeutic strategies. The data generated will advance the field by enhancing our understanding of gamma-herpesvirus latency to facilitate the development of therapeutic strategies for the human gamma-herpesviruses.

描述（由申请人提供）：人类γ-疱疹病毒、EB病毒（EBV）和卡波西肉瘤相关疱疹病毒（KSHV）引起与多种恶性肿瘤的发展相关的持续感染。尽管感染的裂解阶段是由免疫系统控制的，但病毒通过建立终生潜伏期来逃避免疫，即使在免疫能力强的宿主中也是如此。感染的病理后果主要与病毒潜伏期有关，并且没有可用的预防性或治疗性疫苗。 B细胞是潜伏病毒的主要储存库，与EBV感染相关的一个重要临床问题是移植后免疫抑制后发生B细胞淋巴增殖性疾病和/或B细胞淋巴瘤。临床使用利妥昔单抗（抗 B 细胞抗体疗法）针对移植后恶性肿瘤中 EBV 转化的 B 细胞，取得了有希望的结果，这表明抗 B 细胞疗法可以预防性地用于显着降低潜在负荷，甚至清除潜在负荷。移植前宿主的潜伏期。为了测试这种治疗方法和其他治疗方法，有必要了解维持长期潜伏期的机制，这可以在实验动物模型中得到最好的阐明。 Gamma HV68（也称为 MHV-68）是一种自然产生的啮齿动物 γ-疱疹病毒，可感染实验室小鼠，为进行人类不可能进行的实验提供了一种易于操作的小动物自然感染模型。当前的提案利用鼠标模型来解决维持延迟的机制。重要的是，我们将测试可以从受感染宿主中清除潜伏病毒的假设。在目标 1 中，我们将确定病毒再激活和再感染是否有助于维持 B 细胞、巨噬细胞和树突状细胞的长期潜伏期。在目标 2 中，我们将确定使用 B 细胞消耗抗体来模拟利妥昔单抗治疗（无论是否使用抗病毒药物）是否可以减少或消除长期潜伏期。公共卫生相关性：γ-疱疹病毒是致癌病毒，在人群中广泛传播，并与恶性肿瘤的发生有关。对成熟的γ-疱疹病毒感染小鼠模型的分析为剖析病毒潜伏期重新激活的基本事件提供了重要工具，并可作为测试概念验证治疗策略的体内模型。生成的数据将通过增强我们对γ-疱疹病毒潜伏期的理解来推动该领域的发展，从而促进人类γ-疱疹病毒治疗策略的开发。