A recombinant virus approach for gamma herpesvirus oncogenesis

用于伽马疱疹病毒肿瘤发生的重组病毒方法

• 批准号: 8638543
• 负责人: Pinghui Feng
• 金额: $ 24.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638543
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Antiviral Agents; B-Cell Lymphomas; Bacterial Artificial Chromosomes; Cells; Common Neoplasm; Complement; Coupled; Cyclosporine; Data; Disease; Disease Progression; Dissection; Engineering; Event; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Genetic Transcription; Goals; Herpesviridae Infections; Homologous Gene; Human; Human Herpesvirus 4; Human Herpesvirus 8; Human herpesvirus 8 G protein-coupled receptor; Immune; Immunity; Infection; Interleukin 8A Receptor; Kaposi Sarcoma; Kinetics; Knock-out; Laboratories; Laboratory mice; Lesion; Ligand Binding; Ligands; Liver; Lung; Lymphoproliferative Disorders; Malignant Neoplasms; Modeling; Molecular; Monitor; Morbidity - disease rate; Mouse Strains; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; Nude Mice; Oncogenes; Oncogenic; Organ; Pathogenesis; Patients; Phosphorylation; Phosphotransferases; Recombinants; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Spleen; System; T-Lymphocyte; Testing; Transcriptional Activation; Transgenic Mice; Tumorigenicity; Viral; Virus Diseases; Work; base; gammaherpesvirus; in vivo; insight; interest; lytic replication; mortality; mouse model; pathogen; primary effusion lymphoma; public health relevance; receptor expression; recombinant virus; research study; tumor; tumorigenesis; tumorigenic; virus host interaction

Abstract Human Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are the leading etiological agents that cause morbidity and mortality in immune compromised patients. Currently, we do not have good animal models to study these oncogenic human pathogens. Closely related to human KSHV and EBV, murine gamma herpesvirus 68 infects laboratory mice, undergoes robust lytic replication in the lung and establishes persistent infection in the spleen. This provides an excellent small animal model to study gamma herpesvirus infection in vivo. However, murine gamma herpesvirus 68 infection causes limited pathogenesis in laboratory mouse strains, offering minimal insights into diseases, e.g., cancers associated with KSHV and EBV. The goal of this study is to develop a surrogate system that enables the interrogation of host-virus interactions in virally-induced tumorigenesis, in the context of viral infection. Accordingly, the specific aims of this proposal are to: 1) engineer recombinant murine gamma herpesvirus 68 that carries the prominent KSHV oncogene, kGPCR, and examine viral replication in culture and infection in mice, and 2) to evaluate the tumorigenicity of recombinant gamma herpesvirus 68 in normal and immune- compromised mice, focusing on lymphoproliferative and Kaposi's sarcoma-like diseases. This study will provide a valuable platform to dissect viral oncogenesis that is truly induced during viral infection.

抽象的 人类卡波西肉瘤相关疱疹病毒 (KSHV) 和 Epstein-Barr 病毒 (EBV) 是导致免疫疾病发病和死亡的主要病原体 受损的患者。目前，我们还没有好的动物模型来研究这些 致癌人类病原体。与人类 KSHV 和 EBV、鼠伽玛病毒密切相关 疱疹病毒 68 感染实验室小鼠，在肺部进行强烈的裂解性复制， 造成脾脏持续感染。这提供了一种优秀的小动物 研究体内γ疱疹病毒感染的模型。然而，鼠伽玛 疱疹病毒 68 感染导致实验室小鼠品系的发病机制有限， 对疾病（例如与 KSHV 和 EBV 相关的癌症）提供的了解很少。 本研究的目标是开发一种代理系统，能够审问 在病毒感染的情况下，病毒诱导的肿瘤发生中宿主与病毒的相互作用。 因此，该提案的具体目标是：1）工程重组小鼠 γ 疱疹病毒 68 携带突出的 KSHV 癌基因、kGPCR 和 检查培养物中的病毒复制和小鼠感染，2) 评估 重组 γ 疱疹病毒 68 在正常和免疫组中的致瘤性 受损小鼠，重点关注淋巴增殖性和卡波西肉瘤样 疾病。这项研究将为剖析病毒肿瘤发生提供一个有价值的平台 真正是在病毒感染期间诱导的。