T-CELL FUNCTION IN PEDIATRIC AIDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类免疫缺陷病毒1型(HIV-1)的母体传播是儿童HIV-1感染的大多数病例。大约75%到85%的围产期感染HIV-1的婴儿发展为缓慢进展的感染病程，CD4下降缓慢。相比之下，10%至25%的受感染婴儿在出生后两年内迅速进展感染，早期CD4+T细胞耗尽，随后死亡。第一组维持对病毒复制的一些控制的机制尚不清楚。以前的研究表明，细胞毒性T淋巴细胞、中和抗体和抗体依赖的细胞毒作用在成人病毒复制的早期控制中发挥了作用，但婴儿感染HIV后前6个月的CD8+CTL反应很少观察到，抗HIV抗体反应也非常有限。科学家推测，儿童对艾滋病的易感性是由于“他们的免疫系统不成熟”。然而，人类临床研究中固有的各种伦理和实际考虑因素使得严格解决儿童艾滋病的这些问题变得困难。 这项建议的目的是利用感染致病或非致病的猴免疫缺陷病毒(SIV)株的新生猴子来仔细确定与未感染的NA年龄匹配的新生儿相比，T细胞组成和功能的发育变化。我们将使用优化的多参数流式细胞术来更好地表征SIV感染的新生儿猕猴的早期病毒特异性T细胞反应。 具体目标包括： 具体目标1：研究SIV感染新生猕猴早期SIV特异性T淋巴细胞反应的动态和激活；表征SIV特异性T淋巴细胞在特定宿主组织中的分布和频率；以及检查这种反应是否存在任何功能损害 特定目的2：建立新生儿SIV经口传播模型以模拟HIV-1母婴传播，以更好地了解新生儿和婴儿经口传播的机制和粘膜宿主的免疫反应。 了解免疫反应未能清除或控制艾滋病感染的原因，不仅对了解疾病的发病机制，而且对设计适当的治疗干预措施都很重要。这些信息应该会增强我们对疾病进展的基本了解，并有助于了解感染艾滋病毒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. 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. Maternal transmission of human immunodeficiency virus type 1 (HIV-1) accounts for most cases of pediatric HIV-1 infection. Approximately 75 to 85% of perinatally HIV-1-infected infants develop a slowly progressive course of infection with a slow CD4 decline. In contrast, 10 to 25% of infected infants develop rapidly progressive infection with early CD4+ T-cell depletion followed by death within the first two years of life. The mechanism whereby the first group maintains some control over viral replication is not understood. Previous studies have implicated the role of cytotoxic T lymphocytes, neutralizing antibody and antibody-dependent cellular cytotoxicity in the early control of viral replication in adults, but CD8+ CTL responses in the first six months of HIV infection in infants are rarely observed and anti-HIV antibody responses very limited. Scientists have speculated that susceptibility of children to AIDS is due to the "immaturity of their immune system". However, a variety of ethical and practical considerations inherent in human clinical studies make it difficult to rigorously address these issues in Pediatric AIDS. The goal of this proposal is to use newborn monkeys infected with a pathogenic or non-pathogenic strain of simian immunodeficiency virus (SIV) to carefully define developmental changes in T cells composition and function compared to uninfected na¿ve aged-matched neonates. We will use optimized multiparameter flow cytometry assays to better characterize the early virus-specific T cell responses in SIV-infected newborn macaques. Specific aims include: Specific aim 1: To investigate the dynamics and activation of SIV-specific T lymphocyte responses in early SIV infection in neonatal macaques; to characterize the distribution and frequency of SIV-specific T lymphocytes in specific host tissues; and, to examine if there are any functional impairments of the response Specific aim 2: To develop an oral SIV transmission model in neonate macaques to mimic mother-to-child transmission of HIV-1 to gain a better understanding of mechanisms of oral transmission and mucosal host immune responses in newborns and infants. Understanding why the immune responses fail to clear or control the AIDS infection is important not only to understand the pathogenesis of the disease but also to design appropriates therapeutic interventions. This information should enhance our basic understanding of disease progression and help to understand the immune responses in HIV-infected newborns and infants.