THYMIC FACTORS IN PEDIATRIC HIV DISEASE PROGRESSION

儿科艾滋病毒疾病进展中的胸腺因素

• 批准号: 2517313
• 负责人: FRANCIS K LEE
• 金额: $ 14.32万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2517313
• 关键词: CD antigens; CD34 molecule; CD4 molecule; CD8 molecule; cell sorting; child (0-11); genetic markers; helper T lymphocyte; hematopoietic stem cells; human subject; infant human (0-1 year); neutralizing antibody; nucleic acid sequence; pathologic process; pediatric AIDS; phenotype; thymus; virus antigen; virus load

DESCRIPTION: The overall goal of this applicaton is to obtain a better understanding of the HIV pathogenesis which leads to rapid disease progression in infected children. A subset of HIV-infected children have much more rapid disease progression than adults for still unexplained reasons. The applicants postulate that some young children with early and rapid disease progression may have early disruption of the thymic microenvironment by HIV, resulting in a reduced reservoir of post-thymic lymphocytes. The heavy demand of CD4+ cell regeneration to compensate for HIV-induced destruction leads to rapid exhaustion of this reduced reservoir and early disease progression. Supporting this hypothesis are the applicants' observations that: (1) there is a marked decrease in the CD4+RA+("naive") T lymphocytes in some infected infants, suggesting an intrathymic viral effect; and (2) that many of the earliest progressors of pediatric AIDS have pre-AIDS immunophenotypic profiles similar to those found in children with the DiGeorge congenital thymic anomaly (decrease in CD4+ T cells, as well as in CD8+ T cells and CD5+ B cells). Work in SCID-hu mouse model done by other researchers suggests that there are divergent effects on human thymocyte maturation by HIV-1, depending on the viral strain. The applicants postulate that HIV-1 strains from this subset of rapid progressors may be more disruptive to the thymic microenvironment. There are four specific aims described: (1) to study prospectively immunophenotypic profiles to identify cohort of infants with patterns consistent with early thymic defects (CD4+, CD8+, CD5+ decline) and compare the disease course of these infants with others with more common profiles (CD4+ decline, CD8+ increase); (2) to compare infection of thymic tissue and disruption of the thymic environment observed in vitro with viral isolates from infants and children with early versus slow progression; (3) to compare the effect of infection with different isolates on the maturation of CD34+ stem cells in thymic culture; and (4) to correlate the observations regarding immunophenotypic profiles and thymic culture with measures of viral burden, neutralizing antibody, and induction of CD69 expression on CD8+ cells following HIV antigen exposure as a marker for HIV-specific CD8+ lymphocyte responses. In the proposed studies, the investigators will attempt to identify rapid progressors, particularly children with immunophenotypic profile consistent with early thymic defects and will evaluate potential differences of their HIV-1 strains from that of delayed progressors. Primary viral isolates will be compared for effects on fetal, neonatal and young infant thymic tissues, using an in vitro model of thymic slices cultures, with or without stem cell co-cultures. Difference in disruption of the thymic microenvironment, and ability to support thymic maturation of lymphocytes from stem cells will be assessed by immunohistochemical and in situ molecular methods. Viral strains with distinct patterns of thymic "virulence" will be analyzed for genetic markers using nucleotide sequence data that have been obtained on these viral isolates. Correlation studies will include quantitation of viral load, neutralizing antibodies and HIV-specific CD8+ lymphocyte responses (using novel FACS analyses of CD69 activation markers). Identifying the mechanism for rapid disease in children is important for designing therapeutic strategies, including possibly thymic transplantation.

描述：该应用程序的总体目标是获得更好的 了解导致快速发病的艾滋病毒发病机制 受感染儿童的进展。一部分感染艾滋病毒的儿童 疾病进展速度比成人快得多 无法解释的原因。申请人假设一些年幼的孩子 随着疾病的早期和快速进展，可能会早期破坏 HIV 影响胸腺微环境，导致胸腺微环境减少 胸腺后淋巴细胞。 CD4+细胞再生的巨大需求 补偿艾滋病毒引起的破坏会导致这种能力迅速耗尽 减少储存和早期疾病进展。支持这个 假设是申请人的观察：（1）有一个明显的 一些受感染婴儿的 CD4+RA+（“原始”）T 淋巴细胞减少， 提示胸腺内病毒效应； (2) 许多 儿童艾滋病最早进展者具有艾滋病前免疫表型 特征与 DiGeorge 先天性儿童的特征相似 胸腺异常（CD4+ T 细胞以及 CD8+ T 细胞和 CD5+ B 细胞）。其他研究人员在 SCID-hu 小鼠模型中所做的工作 表明对人类胸腺细胞成熟有不同的影响 由 HIV-1 感染，具体取决于病毒株。申请人假设 来自这组快速进展者的 HIV-1 毒株可能更多 破坏胸腺微环境。具体目标有四个 描述： (1) 前瞻性研究免疫表型谱以确定队列 具有与早期胸腺缺陷一致的模式的婴儿（CD4+， CD8+、CD5+ 下降）并将这些婴儿的病程与 其他具有更常见的特征（CD4+ 下降，CD8+ 增加）； (2) 比较胸腺组织的感染和胸腺的破坏 用婴儿和病毒分离物在体外观察到的环境 进展较早与进展缓慢的儿童； (3) 比较不同菌株的感染效果 胸腺培养物中 CD34+ 干细胞的成熟；和 (4) 将免疫表型谱的观察结果与 胸腺培养，测量病毒负荷、中和抗体和 HIV抗原暴露后CD8+细胞上CD69表达的诱导 作为 HIV 特异性 CD8+ 淋巴细胞反应的标志物。 在拟议的研究中，研究人员将尝试快速识别 进展者，特别是具有免疫表型特征的儿童 与早期胸腺缺陷一致，并将评估潜力 他们的 HIV-1 毒株与延迟进展者的区别。 将比较初级病毒分离株对胎儿、新生儿的影响 和年幼婴儿胸腺组织，使用胸腺体外模型 切片培养物，有或没有干细胞共培养物。差异在于 胸腺微环境的破坏和支持胸腺的能力 干细胞淋巴细胞的成熟将通过以下方式进行评估 免疫组织化学和原位分子方法。病毒株具有 将分析胸腺“毒力”的不同模式进行遗传分析 使用从这些上获得的核苷酸序列数据进行标记 病毒分离株。相关性研究将包括病毒的定量 负荷、中和抗体和 HIV 特异性 CD8+ 淋巴细胞反应 （使用 CD69 激活标记的新型 FACS 分析）。识别 儿童快速发病的机制对于设计很重要 治疗策略，包括可能的胸腺移植。