Herpesvirus latency and reactivation in macaque models of human disease

描述(由申请人提供)：这项与资源相关的(R24)赠款建议描述与人类疱疹病毒8型(HHV8)相关的两种截然不同的猕猴横纹病毒谱系，RV1和RV2。已经开发了新的试剂和检测方法来研究这些病毒在人类疾病猕猴模型中的潜伏和重新激活。我们建议的研究最初集中在猪尾猕猴的Rhadino病毒上，这是华盛顿国家灵长类研究中心保存的最常见的猕猴物种。猕猴弹状病毒在圈养猕猴种群中高度流行，并表达与宿主细胞蛋白相互作用的病毒蛋白，包括那些影响宿主免疫系统的蛋白。因此，这些病毒的存在可能会使对人类疾病猕猴模型数据的解释复杂化和/或混淆。在免疫抑制的猕猴模型中，干扰的可能性可能最大。RV1和RV2都与猕猴的重大疾病有关，这些疾病与人类HHV8相关的癌症非常相似，包括卡波西肉瘤(KS)、淋巴瘤和多中心Castleman病。因此，猕猴横纹病毒的特征，包括能够评估其生物学和生命周期的特定试剂和分析的发展，是发展与疱疹病毒相关的猕猴模型和成功地将猕猴用作其他疾病模型的重要前提。具体地说，我们建议1)完成猕猴RV1 RhadinoVirus RFHVMn的基因组序列，2)建立特异的检测方法来研究猕猴RV1和RV2 RhadinoVirus的感染和流行，3)表征实验中RV1和RV2 RhadinoVirus在体内的感染情况，以及4)通过免疫抑制剂治疗来表征现有RV1和RV2 RhadinoVirus在猕猴体内的潜伏感染的重新激活。

DESCRIPTION (provided by applicant): This resource-related (R24) grant proposes to characterize the two distinct lineages of macaque rhadinovirus related to human herpesvirus 8 (HHV8), RV1 and RV2. New reagents and assays have been developed to study the latency and reactivation of these viruses in macaque models of human disease. Our proposed studies initially focus on the rhadinoviruses of the pig-tailed macaque, the most common macaque species maintained at the Washington National Primate Research Center. The macaque rhadinoviruses are highly prevalent in captive macaque populations and express viral proteins that interact with host cellular proteins, including those affecting the host immune system. Thus, the presence of these viruses may complicate and/or confound the interpretation of data from macaque models of human disease. The potential for interference may be most acute in macaque models of immunosuppression. Both RV1 and RV2 have been associated with significant diseases in macaques that closely resemble cancers associated with HHV8 in humans, including Kaposi sarcoma (KS), lymphoma and multicentric Castleman's disease. Thus, the characterization of the macaque rhadinoviruses, including the development of specific reagents and assays that enable the evaluation of their biology and life cycles, is an important prerequisite for the development of herpesvirus-related macaque models and to the successful use of macaques as models of other diseases. Specifically, we propose to 1) Complete the genomic sequence of the macaque RV1 rhadinovirus, RFHVMn, 2) Develop specific assays to study the infection and prevalence of the macaque RV1 and RV2rhadinoviruses, 3) Characterize the experimental infection of naive macaques with RV1 and RV2rhadinoviruses in vivo, and 4) Characterize the reactivation of existing latent infections of RV1 and RV2rhadinoviruses in macaques by treatment with immunosuppressive agents.