A MONKEY MODEL FOR ANTI-CYTOMEGALOVIRUS THERAPY

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。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。列出的机构是 中心，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非人灵长类动物模型，以评价人巨细胞病毒（HCMV）的治疗，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。对于这些研究，我们使用恒河猴CMV（RhCMV）感染恒河猴。我们之前已经通过体外研究确定，RhCMV和HCMV对批准用于人类HCMV治疗的药物的敏感性几乎相同。在过去的一年中，我们评估了FDA批准的药物西多福韦（CDV）在猕猴急性感染期间的抗RhCMV活性。进行药物动力学研究以确定CDV给药的适当剂量和途径。 最佳剂量为5 mg/kg，每周一次，静脉内给药，相当于用于人类HCMV治疗的CDV剂量。用CDV处理10只RhCMV感染的猕猴，并与10只模拟处理的对照组进行比较。相对于模拟处理的对照，处理的动物中的病毒载量减少超过99%。这些研究验证了用于HCMV治疗的体内研究的RhCMV模型。

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 to evaluate 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. For these studies we are using Rhesus CMV (RhCMV) infection of rhesus macaques. We have previously established with in vitro studies that RhCMV and HCMV are nearly identical in susceptibility to the drugs that are approved for HCMV therapy in humans. In the past year we have evaluated the FDA approved drug cidofovir (CDV) for anti-RhCMV activity in macaques during acute infection. A pharmokinetics study was performed to establish an appropriate dose and route of CDV administration. The optimal dose was 5 mg/kg given intraveneously, once weekly, which is equivalent to the CDV dose used for HCMV therapy in humans. Ten RhCMV-infected macaques were treated with CDV and compared to ten mock-treated controls. Virus loads in the treated animals were reduced more than 99% relative to mock-treated controls. These studies validate the RhCMV model for in vivo studies of HCMV therapy.