A Monkey Model for Anti-Cytomegalovirus Therapy

描述（由申请人提供）：该项目的长期目标是开发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)能够快速体内评估有希望的抗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，通过评估健康恒河猴急性和持续性感染的参数变化，可以用于抗巨细胞病毒药物的快速和敏感的体内评价。

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.