T-CELL FUNCTION IN PEDIATRIC AIDS

这个子项目是许多研究子项目中的一个 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。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 母婴传播的人类免疫缺陷病毒1型（HIV-1）占大多数情况下，儿童HIV-1感染。 大约75%至85%的围产期HIV-1感染的婴儿发展为缓慢进行性感染过程，伴随着缓慢的CD 4下降。 相比之下，10%至25%的感染婴儿发展为快速进行性感染，早期CD 4 + T细胞耗竭，随后在生命的头两年内死亡。第一组维持对病毒复制的某种控制的机制尚不清楚。以往的研究表明，细胞毒性T淋巴细胞、中和抗体和抗体依赖性细胞毒性在成人病毒复制的早期控制中发挥作用，但在婴儿HIV感染的前6个月很少观察到CD 8 + CTL应答，抗HIV抗体应答非常有限。科学家们推测，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践考虑使得在儿科艾滋病中严格解决这些问题变得困难。 该提案的目标是使用感染了猴免疫缺陷病毒（SIV）的致病性或非致病性菌株的新生猴，与未感染的幼稚年龄匹配的新生猴相比，仔细定义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检测，以更好地表征SIV感染的新生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特异性T淋巴细胞在新生猕猴感染SIV早期的动态变化和活化情况，以及SIV特异性T淋巴细胞在特定宿主组织中的分布和频率，并检测是否存在SIV特异性T淋巴细胞应答的功能障碍 具体目标2：建立新生猕猴中SIV经口传播模型，模拟HIV-1母婴传播，以更好地了解新生儿和婴儿经口传播和粘膜宿主免疫反应的机制。 了解为什么免疫反应不能清除或控制艾滋病感染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。这些信息应加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.