A Monkey Model for Anti-Cytomegalovirus Therapy

描述(申请人提供)：该项目的长期目标是开发一种用于人类巨细胞病毒(HCMV)治疗研究的非人类灵长类动物模型，该模型将1)实现对有前景的抗HCMV药物的体内快速评估，2)允许在临床相关条件下开发HCMV的治疗策略。之所以选择恒河猴巨细胞病毒(RhCMV)感染猕猴是因为，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，但它会导致免疫系统受损的猕猴的大量发病率。初步研究表明，RhCMV和HCMV对已批准的抗CMV药物和苯并咪唑核糖核苷(BR)的几个新成员的体外敏感性几乎相同。我们推测，恒河猴感染人巨细胞病毒可以通过评估健康猕猴急性和持续感染参数的变化，来快速、灵敏地进行体内抗CMV药物的评价。 免疫能力强的猕猴。我们建议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，我们将通过实时荧光聚合酶链式反应(Real-time PCR)来量化在接受CDV或BR治疗的猴子初次感染期间，与对照组相比，血浆中RhCMV基因组拷贝数的减少。 通过对宿主抗巨细胞病毒抗体的分析，将提供药物治疗效果的另一种衡量标准 免疫反应。在目标2中，CDV和BR在持续的RhCMV感染期间的疗效将通过减少口腔和生殖器粘膜中RhCMV的脱落频率和滴度来量化。 最终，我们预测，这个模型可以用来测试艾滋病、移植或胎儿发育过程中CMV感染的治疗方法，这是可以实验操纵的。

DESCRIPTION (provided by applicant): 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.