A recombinant virus approach for gamma herpesvirus oncogenesis

摘要 人类卡波西肉瘤相关疱疹病毒(KSHV)和EB病毒(EBV) 是导致免疫疾病发病率和死亡率的主要病原体 有危险的病人。目前，我们还没有很好的动物模型来研究这些 致癌的人类病原体。与人KSHV和EBV、小鼠伽马密切相关 疱疹病毒68感染实验室小鼠，在肺部经历强劲的裂解复制，并 在脾内建立持续性感染。这提供了一种极好的小动物 研究体内伽玛疱疹病毒感染的模型。然而，小鼠伽马 疱疹病毒68感染在实验室小鼠品系中引起有限的致病作用， 提供对疾病的最低限度的洞察，例如与KSHV和EBV相关的癌症。 这项研究的目标是开发一种代理制度，使审问 在病毒感染的背景下，病毒诱导的肿瘤发生中的宿主-病毒相互作用。 因此，这一提议的具体目的是：1)工程重组小鼠 携带KSHV癌基因kGPCR的伽马疱疹病毒68，以及 检测病毒在培养中的复制和小鼠的感染，以及2)评估 重组伽玛疱疹病毒68在正常和免疫小鼠体内的致瘤性 受损小鼠，专注于淋巴增生性和卡波西肉瘤样 疾病。这项研究将为剖析病毒的致癌作用提供一个有价值的平台 在病毒感染期间真正诱导的。

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.