In Vivo Characterization of the Pathogenesis of Modified RhCMV Vectors (Pathogene

说明)： 将RhCMV作为外来抗原的疫苗载体转化为人体试验的一个关键问题是 证明了RhCMV矢量被充分衰减，从而表现出减少的参数 病毒式增长。对于那些没有完全功能的免疫系统的猴子来说尤其如此 重述人类状况的临床情景。除了免疫中的无症状感染 有能力的宿主，改良的RhCMV疫苗载体应该会在免疫的猴子中引起较少的疾病 因混合感染SIV或医源性免疫抑制而缺乏，以及胎儿宫内携带RhCMV 感染。此核心将评估作为复制和安全性父提案的一部分构建的载体 在两种免疫妥协的猴子模型中：与胎儿发育相关的免疫不成熟，以及 移植相关的免疫抑制。核心C的任务是定义复制和 重组人巨细胞病毒/SIV载体在胚胎和成年猴体内的致病潜能胎儿致病模型：人巨细胞病毒 长期以来一直被认为是对胎儿的传染性威胁，特别是在初级HCMV的背景下 母亲的感染。我们在恒河猴宫内巨细胞病毒致病模型上所做的工作表明 暴露于巨细胞病毒的胎儿猕猴与儿童表现出几乎相同的发育异常 先天性感染人巨细胞病毒。胎儿对复制巨细胞病毒极为敏感，并呈现出一种 灵敏的体内评价修饰载体的复制和致病潜能。成虫 致病模式：人巨细胞病毒也是致死于实体器官和 骨髓移植受者。与移植相关的巨细胞病毒再激活类似，猿猴巨细胞病毒 在免疫抑制的非人类灵长类动物(NHP)中观察到接受同种异体移植或 异种移植物。我们已经证明，医源性免疫抑制后猴巨细胞病毒的重新激活导致 到严重的肺炎和肺血管病。作为RhCMV减毒的另一种衡量标准 项目1和2的构建，是人类主要候选载体的致病潜力 疗效试验将在成年动物免疫功能低下的情况下进行调查。 相关性(请参阅说明)： 这一核心将严格测试RhCMV载体的复制和致病作用的残留水平。这个 该核心的结果将是至关重要的将候选载体推进到人类临床试验 评价修饰后的重组人巨细胞病毒载体的体内生长潜能。我们与恒河猴的生产史 HCMV模型证明了我们有能力满足项目的时间进度。 项目/绩效网站(S)(如果需要额外空间，请使用项目/绩效网站格式页面) 项目/绩效

instmctions): A critical issue related to the translation of RhCMV as a vaccine vector for foreign antigens to human trials is the demonstration that the RhCMV vectors are sufficiently attenuated so as to exhibit reduced parameters of viral growth. This is particularly true for those monkeys without a fully functional immune system under clinical scenarios that recapitulate the human condition. In addition to asymptomatic infections in immune competent hosts, modified RhCMV vaccine vectors should induce less disease in monkeys that are immune deficient by coinfection with SIV or iatrogenically immunosuppressed, and fetuses with intrauterine RhCMV infection. This Core will evaluate vectors constructed as part of the parent proposal for replication and safety in two monkey models of immune compromise: immune immaturity associated with fetal development, and transplant-associated immune suppression. The mission of Core C is to define the replication and pathogenic potentials of RhCMV/SIV vectors in fetal and adult monkeys. Fetal Pathogenesis Model: HCMV has long been recognized as an infectious threat to the fetus, especially in the context of primary HCMV infection of the mother. Our work with the rhesus model of intrauterine HCMV pathogenesis has shown that fetal macaques exposed to RhCMV exhibit nearly identical developmental abnormalities as children congenitally infected with HCMV. The fetus is acutely permissive to replicating RhCMV and presents a sensitive in vivo evaluation ofthe replication and pathogenic potentials ofthe modified vectors. Adult Pathogenesis Model: HCMV is also the primary infectious cause of morbidity and mortality in solid organ and bone marrow transplant recipients. Similar to transplant-associated reactivation of HCMV, simian CMV disease has been observed in immunosuppressed nonhuman primates (NHP) receiving either allografts or xenografts. We have shown that reactivation of simian CMV following iatrogenic immunosuppression leads to severe pneumonitis and pulmonary vasculopathy. As another measure of attenuation of the RhCMV constructs of Projects 1 and 2, the pathogenic potential of vectors that are the lead candidates for human efficacy trials will be investigated in the context of depressed immune function in adult animals. RELEVANCE (See instructions): This Core will rigorously test the RhCMV vectors for residual levels of replication and pathogenesis. The results ofthis Core will be essential for moving candidate vectors forward to human clinical trials by critically evaluating the growth potential ofthe modified RhCMV vectors in vivo. Our productive history with the rhesus model of HCMV demonstrates our ability to meet the time schedule of the Project. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/Perfonnance Site Fomiat Page) Project/Performance