Herpesvirus latency and reactivation in macaque models of human disease

描述（由申请人提供）：该资源相关（R24）拨款旨在描述与人类疱疹病毒8 （HHV8）、RV1和RV2相关的两种不同的猕猴横纹肌病毒谱系。已经开发了新的试剂和分析方法来研究这些病毒在人类疾病的猕猴模型中的潜伏期和再激活。我们提出的研究最初集中在长尾猕猴的rhadino病毒上，长尾猕猴是华盛顿国家灵长类动物研究中心最常见的猕猴物种。猕猴横纹肌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，包括影响宿主免疫系统的病毒蛋白。因此，这些病毒的存在可能使对人类疾病猕猴模型数据的解释复杂化和/或混淆。潜在的干扰可能是最严重的猕猴模型的免疫抑制。RV1和RV2都与猕猴的重要疾病相关，这些疾病与人类与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rhadinovirus的特征表征，包括开发能够评估其生物学和生命周期的特定试剂和检测方法，是开发疱疹病毒相关猕猴模型和成功使用猕猴作为其他疾病模型的重要先决条件。具体来说，我们建议：1)完成猕猴RV1横纹肌病毒（RFHVMn）的基因组序列；2)建立研究猕猴RV1和rv2横纹肌病毒感染和流行的特异性检测方法；3)鉴定猕猴体内RV1和rv2横纹肌病毒的实验感染特征；4)鉴定免疫抑制剂治疗猕猴体内RV1和rv2横纹肌病毒潜伏感染的再激活特征。

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.