PACTG: P1006

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。在HIV-1感染的儿童开始接受高效抗逆转录病毒治疗(HAART)后，CD4T细胞显著增加。然而，在HAART期间，还没有大规模发表的儿童研究来描述HIV感染儿童的免疫恢复动态。需要一项多中心研究来检查HAART启动后再生的T细胞的表型和功能，以进一步评估初步数据支持的几个假设。这些初步数据支持这样的假设：1)严重免疫衰竭的儿童在开始HAART后1-2年内会产生大量的CD4T细胞(尤其是那些原始表型的细胞)；2)T细胞的恢复依赖于治疗前3个月病毒载量的大幅下降，但不需要在治疗6个月后持续抑制病毒复制；3)免疫反应的自发恢复不会由于记忆T细胞的克隆缺失而发生；4)新获得的CD4T细胞可以在抗原暴露后产生反应。因此，本研究将检测HAART启动后再生的T细胞的表型，并通过评估T细胞对新抗原和召回抗原的反应来评估其功能。一个需要解决的具体问题是，当外周记忆T细胞可能增加时，儿童免疫功能的恢复是否发生在治疗的早期。备选地，记忆T细胞克隆可以不是来自外周记忆T细胞的扩张，而是可以从最近被教育成为记忆细胞的原始T细胞衍生而来。为了进一步剖析HAART期间新生成的T细胞的功能，将测试细胞对召回抗原(破伤风)、主要免疫原(甲型肝炎)和环境抗原(念珠菌)的免疫反应。新产生的T细胞对破伤风类毒素和一种新的T细胞依赖抗原(甲型肝炎)加强免疫的反应能力。

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. A significant increase in CD4 T cells occurs after the initiation of highly active antiretroviral therapy (HAART) in HIV-1 infected children. However, there are no large published studies in children delineating the dynamics of immune recovery in HIV-infected children during HAART. A multi-center study powered to examine the phenotype and function of T cells regenerated post - HAART initiation is needed to further assess several assumptions supported by the preliminary data. These preliminary data support the assumptions that 1) children with severe immunodepletion will develop significant numbers of CD4 T cells (particularly those of the naive phenotype) for 1-2 years after initiating HAART; 2) the recovery of T cells is dependent on a significant decrease in viral load in the first 3 months of therapy but does not require sustained suppression of viral replication after 6 months of therapy; 3) the spontaneous recovery of immunologic responses will not occur due to the clonal deletion of memory T cells; and 4) newly acquired CD4 T cells can develop responses upon antigenic exposure. This study will therefore examine the phenotype of T cells regenerated post initiation of HAART and assess their function by evaluating T cell responses to new antigens and recall antigens. One specific question to be addressed will be whether recovery of immunologic function in children occurs early in therapy when an increase in peripheral memory T cells is likely to occur. Alternatively, memory t cell clones may not be from expansion of peripheral memory T cells but rather may be derived from naive T cells that were recently educated to become memory cells. In order to further dissect function of newly generated T cells during HAART, cell mediated immune responses to a recall antigen (tetanus), a primary immunogen (hepatitis A) and an environmental antigen (Candida), will be tested. The ability of the newly generated T cells to respond to booster immunizations with tetanus toxoid and a new antigen T cell dependent antigen (hepatitis A).