A MONKEY MODEL FOR ANTI-CYTOMEGALOVIRUS THERAPY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：本项目的长期目标是建立一种非人类灵长类动物模型，用于研究人类巨细胞病毒（HCMV）的治疗方法，这将使1)能够快速在体内评估有前途的抗HCMV药物，2)允许在临床相关条件下开发HCMV的治疗策略。选择恒河巨细胞病毒（RhCMV）感染的恒河猴作为本项目的研究对象，是因为与人类的HCMV一样，RhCMV通常会在健康个体中建立终身持续但无症状的感染，但它会在免疫系统受损的恒河猴中引起大量发病率。初步研究表明，RhCMV和HCMV在体外对已批准的抗cmv药物和一种有前途的新类别苯并咪唑核糖核苷（BR）的几个成员的敏感性几乎相同。我们假设，通过评估健康、免疫功能正常的恒河猴急性和持续感染的参数变化，恒河猴RhCMV感染可用于快速、敏感的体内抗cmv药物评估。我们建议用一种特性明确且已获批准的抗巨细胞病毒药物Cidofovir （CDV）来评估该模型，并表征一种有前景的BR的抗巨细胞病毒活性。在第1项研究中，我们将通过实时荧光定量PCR方法，量化接受CDV或BR治疗的猴子在原发感染期间血浆中RhCMV基因组拷贝数的减少。另一种衡量药物治疗效果的方法将通过分析宿主抗巨细胞病毒免疫反应来提供。在Aim 2中，CDV和BR在持续RhCMV感染期间的疗效将通过减少口腔和生殖器粘膜RhCMV脱落的频率和滴度来量化。最终，我们预测该模型可用于测试艾滋病、移植或灵长类宿主胎儿发育期间巨细胞病毒感染的治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: The long-range goal of this project is to develop a non-human primate model for studies of therapy for human cytomegalovirus (HCMV) that will 1) enable rapid in vivo evaluation of promising anti-HCMV drugs, and 2) allow development of therapeutic strategies for HCMV under clinically relevant conditions. Rhesus CMV (RhCMV) infection of rhesus macaques was chosen for this project because, like HCMV in humans, RhCMV typically establishes lifelong persistent, but asymptomatic, infections in healthy individuals, but it causes substantial morbidity in macaques with an impaired immune system. Preliminary studies have demonstrated that RhCMV and HCMV are nearly identical in in-vitro susceptibilities to approved anti-CMV drugs and to several members of a promising new class, benzimidazole ribonucleosides (BR). We hypothesize that RhCMV infection of rhesus macaques can be used for rapid and sensitive in vivo evaluation of anti-CMV drugs by assessment of changes in parameters of acute and persistent infection of healthy, immunocompetent macaques. We propose to evaluate the model with one well-characterized and approved anti-CMV drug, Cidofovir (CDV), and to characterize the anti-CMV activity of a promising BR. In Aim 1 we will quantify the reduction in RhCMV genome copy number in plasma by real-time PCR during primary infection in monkeys treated with either CDV or a BR, compared to controls. Another measure of the efficacy of drug treatment will be provided by analysis of host anti-CMV immune responses. In Aim 2 the efficacy of CDV and BR during persistent RhCMV infection will be quantified by reduction of the frequency and titer of RhCMV shed at the oral and genital mucosa. Ultimately, we predict that this model can be used to test therapies for CMV infections during AIDS, Transplantation, or fetal development in a primate host that can be experimentally manipulated.