A MONKEY MODEL FOR ANTI-CYTOMEGALOVIRUS THERAPY

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目的：该项目的长期目标是开发一种用于研究人类巨细胞病毒 (HCMV) 治疗的非人类灵长类动物模型，该模型将 1) 能够快速体内评估有前景的抗 HCMV 药物，2) 允许在临床相关条件下制定 HCMV 治疗策略。该项目选择恒河猴感染恒河猴 CMV (RhCMV)，因为与人类 HCMV 一样，RhCMV 通常会在健康个体中造成终生持续但无症状的感染，但会在免疫系统受损的猕猴中造成严重发病。初步研究表明，RhCMV 和 HCMV 对已批准的抗 CMV 药物以及有前途的新类别苯并咪唑核糖核苷 (BR) 的几个成员的体外敏感性几乎相同。我们假设恒河猴的 RhCMV 感染可通过评估健康、免疫功能正常的猕猴的急性和持续感染参数的变化，用于快速、灵敏地体内评价抗 CMV 药物。我们建议使用一种经过充分表征和批准的抗 CMV 药物西多福韦 (CDV) 来评估该模型，并表征一种有前途的 BR 的抗 CMV 活性。在目标 1 中，我们将通过实时 PCR 来量化用 CDV 或 BR 治疗的猴子初次感染期间与对照相比血浆中 RhCMV 基因组拷贝数的减少情况。药物治疗功效的另一个衡量标准是通过分析宿主抗 CMV 免疫反应来提供。在目标 2 中，CDV 和 BR 在持续性 RhCMV 感染过程中的功效将通过减少口腔和生殖器粘膜排出的 RhCMV 频率和滴度来量化。最终，我们预测该模型可用于在可通过实验操作的灵长类宿主中测试艾滋病、移植或胎儿发育期间巨细胞病毒感染的疗法。

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.