TB INFECTION IN NHP MODEL OF PEDIATRIC AIDS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 结核病是全世界艾滋病患者的主要死因，是与艾滋病毒一起发生的最早的机会性感染之一，是艾滋病毒复制和随后免疫系统恶化的促进剂。每年，全世界有100万儿童新感染结核病，42万儿童感染艾滋病毒。结核分枝杆菌和艾滋病毒的混合感染是一种“受诅咒的二重奏”，是一个日益严重的全球紧急情况。虽然在HIV-1/结核分枝杆菌混合感染患者的结核病治疗过程中使用高效抗逆转录病毒疗法与降低死亡率有关，但它也可能危及生命。 迫切需要一种HIV/结核分枝杆菌混合感染的猴子模型，这样就可以开发出同时对抗两种病原体的鸡尾酒疗法。由于结核病和艾滋病疫苗是为成人开发的，因此幼猴模型也将成为测试这些疫苗在婴儿(以及可能被动将免疫力传递给婴儿的孕妇)中的有效性和安全性的重要工具。 我们在婴儿恒河猴艾滋病模型方面有相当多的经验，在成人恒河猴结核病模型方面也有相当多的经验。我们建议建立和优化恒河猴新生儿/婴儿结核病感染模型，以表征疾病进展的临床、细菌学和免疫学特征。这项工作将在我们的ABSL-3设施中进行，预计将提供足够的数据，以确定足以导致结核病逐渐发展的剂量，而不是太高，以至于动物死亡太快，无法进行实验干预，特别是在合并感染的动物中。 总体目标是建立一种模仿新生儿/婴儿疾病的临床、细菌学和免疫学特征的新生儿非人类灵长类结核病模型。本试点项目的目标是建立和优化结核分枝杆菌在新生儿和婴儿猕猴中的剂量-反应感染，以研究儿童艾滋病新生儿猕猴模型中结核感染的机制。 这些信息应该会增强我们对疾病进展的基本了解，并有助于了解感染结核病的新生儿和婴儿的免疫反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tuberculosis is the leading cause of death in AIDS patients worldwide, is one of the earliest opportunistic infections occurring in conjunction with HIV, and is an accelerant of the replication of HIV and subsequent deterioration of the immune system. Each year, one million children worldwide become newly infected with tuberculosis (TB) and 420,000 with HIV. Co-infection with Mtb and HIV, the "cursed duet," is an increasing global emergency. Although the use of highly active antiretroviral therapy during TB treatment in HIV-1/Mtb co-infected patients is associated with reduced mortality, it can also be in life threatening. A monkey model of HIV/Mtb co-infection is desperately needed so that cocktail treatments can be developed to fight both pathogens simultaneously. As vaccines for TB and AIDS are developed for adults, the infant monkey model also will become important for testing the efficacy and safety of these vaccines in infants (and in pregnant mothers who may transmit immunity to their infants passively). We have considerable experience with the infant rhesus model for AIDS and we also have considerable experience with the adult rhesus model of TB. We propose to establish and optimize a rhesus macaque newborn/infant model for TB infection to characterize the clinical, bacteriological, and immunological characteristics of disease progression. This work, which will be conducted in our ABSL-3 facility, is expected to provide sufficient data to establish a dose that is high enough to cause gradual development of TB disease, and not so high that the animals succumb too quickly to enable experimental interventions, particularly in co-infected animals. The overall goal is to establish a neonatal nonhuman primate tuberculosis model that mimics clinical, bacteriological, and immunological characteristics of newborn/infant disease. The goal of this pilot project is to establish and optimize a M. tuberculosis "dose-response" infection in newborn and infant macaques to investigate the mechanisms of TB infection in the neonatal macaque model of pediatric AIDS. This information should enhance our basic understanding of disease progression and help to understand the immune responses in TB-infected newborns and infants.