A MONKEY MODEL FOR ANTI-CYTOMEGALOVIRUS THERAPY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。目的：该项目的长期目标是开发一种用于人巨细胞病毒（HCMV）治疗研究的非人灵长类动物模型，该模型将1）能够快速体内评价有前途的抗HCMV药物，2）允许在临床相关条件下开发HCMV的治疗策略。本项目选择恒河猴CMV（RhCMV）感染恒河猴，因为与人类中的HCMV一样，RhCMV通常在健康个体中建立终身持续但无症状的感染，但在免疫系统受损的恒河猴中引起大量发病。初步研究表明，RhCMV和HCMV在体外对批准的抗CMV药物和一个有前途的新类别的几个成员，苯并咪唑核糖核苷（BR）的亲和性几乎相同。我们假设，RhCMV感染的恒河猴可以用于快速和敏感的抗CMV药物的体内评价的健康，免疫活性猕猴的急性和持续感染的参数的变化进行评估。我们建议评估模型与一个良好的特点和批准的抗CMV药物，西多福韦（CDV），并表征抗CMV活性的一个有前途的BR。在目标1中，我们将通过实时PCR定量CDV或BR治疗的猴与对照组相比，在初次感染期间血浆中RhCMV基因组拷贝数的减少。通过分析宿主抗CMV免疫应答提供药物治疗功效的另一种测量。在目标2中，将通过降低口腔和生殖器粘膜上RhCMV脱落的频率和滴度来量化CDV和BR在持续性RhCMV感染期间的疗效。最终，我们预测，该模型可用于测试艾滋病，移植或胎儿发育过程中的CMV感染的治疗方法，在灵长类动物宿主中，可以通过实验操作。

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.