SIV--MACAQUE MODEL FOR FETAL INFECTION AND DISEASE

SIV--胎儿感染和疾病的猕猴模型

基本信息

批准号：
3147289
负责人：
Michael A Murphey-Corb
金额：
$ 30.86万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-30 至 1995-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3147289
关键词：
Macaca fascicularis Macaca mulatta Macaca nemestrina birth communicable disease transmission congenital infection disease /disorder model enzyme linked immunosorbent assay genetic strain immunocytochemistry in situ hybridization model design /development placental transfer polymerase chain reaction simian AIDSs simian immunodeficiency virus ultrasonography virulence

项目摘要

Efforts to control the dissemination of HIV through the world's population is compounded by the emergence of HIV infection and disease in the heterosexual population. Vertical transmission of HIV from infected mother to developing fetus is estimated to occur at a rate of 30-50%. A suitable animal model is desperately needed to identify strategies effective in blocking this mode of transmission. We propose to utilize our extensive experience with the SIV: macaque for AIDS to fulfill this need by examining the ability of 2 well-characterized isolates of SIV that vary in virulence, SIV/DeltaB670 and SlVmac clone BK-28, to cross the placenta and cause neonatal disease in 3 species of macaques known to be susceptible to SIV-induced disease as adults. We reason that, although the best isolate is theoretically one that can do both, virulent strains may promote abortion rather than infected neonates. Moreover, a comparison of the effects on the developing fetus of isolates that induce either chronic or acute disease in adult monkeys may provide information useful to our understanding of pathogenic mechanism(s) employed in fetal infection and disease. The incidence of transplacental infection and the nature of fetal disease will be directly compared in three species of macaque (rhesus, cynomolgus, and pigtail) to identify the species best suited for model development. Experiments involving nonhuman primates are labor-intensive and expensive; a higher incidence of transmission means fewer animals per experimental group. In year 1, fetal and neonatal disease induced by the 2 virus isolates will be determined in fetuses inoculated directly by umbilical vein cannulation, caesarian delivered, and hand-reared. This experiment will not only allow characterization of fetal disease but also provide information regarding the optimal virus strain for subsequent studies. Timed mated pregnant females from each species will be inoculated in year 2 during midgestation to identify the optimal species for transplacental infection. The effects of vaginal versus caesarian delivery on perinatal infection will be determined in year 3. A systematic examination of the dissemination of virus from the placenta to the fetal tissues and the pathobiology of fetal disease will be performed in Year 4 in fetuses infected at monthly intervals during gestation. SIV-induced infection and disease will be thoroughly monitored virologically, pathologically, and immunologically by a team of investigators experienced in SIV research using well-documented methodologies. These experiments will elucidate the nature of fetal disease, identify factors responsible for transplacental infection, and provide a working model for maternal-fetal transmission desperately needed for testing drugs and vaccine regima effective in prevention.

努力通过世界各地控制艾滋病毒的传播艾滋病毒感染和疾病的出现使人口变得更加复杂在异性恋人群中。 HIV 的垂直传播来自据估计，发育中的胎儿受感染的母亲的发生率 30-50%。迫切需要合适的动物模型来鉴定有效阻止这种传播方式的策略。我们建议利用我们在 SIV 方面的丰富经验：猕猴治疗艾滋病通过检查 2 个具有良好特征的人的能力来满足这一需求毒力不同的 SIV 分离株、SIV/DeltaB670 和 SlVmac 克隆 BK-28，可穿过胎盘并导致 3 种新生儿疾病已知猕猴成年后容易感染 SIV 引起的疾病。我们原因是，尽管理论上最好的分离物可以做到两者，强毒株可能会促进流产而不是感染新生儿。此外，还比较了对发育中胎儿的影响在成年猴子中诱发慢性或急性疾病的分离株可能提供有助于我们了解致病性的信息胎儿感染和疾病中采用的机制。发病率经胎盘感染与胎儿疾病的性质将直接相关对三种猕猴（恒河猴、食蟹猴和猪尾猴）进行比较以确定最适合模型开发的物种。实验涉及非人类灵长类动物是劳动密集型且昂贵的；更高的传播发生率意味着每个实验组的动物数量较少。第一年，由 2 种病毒分离株引起的胎儿和新生儿疾病将在通过脐静脉直接接种的胎儿中测定插管、剖腹产、人工饲养。这个实验将不仅可以表征胎儿疾病，还可以提供有关后续研究的最佳病毒株的信息。每个物种的定时交配怀孕雌性将在当年接种 2 在妊娠中期确定经胎盘移植的最佳物种感染。阴道分娩与剖腹产对围产期的影响感染情况将在第三年确定。系统检查病毒从胎盘传播到胎儿组织胎儿疾病病理学将在第四年对胎儿进行妊娠期间每月感染一次。 SIV引起的感染将从病毒学、病理学角度对疾病进行彻底监测，由具有 SIV 经验的研究人员团队进行免疫学研究使用有据可查的方法进行研究。这些实验将阐明胎儿疾病的性质，确定导致胎儿疾病的因素经胎盘感染，并为母胎提供工作模型测试药物和疫苗体系迫切需要传播起到了有效的预防作用。