HIV-1 VARIANTS WITHIN PBMC SUBPOPULATIONS IN INFANTS

拟议研究的长期目标是了解 HIV-1致病的分子机制。 儿童接受高 使用蛋白酶抑制剂的主动抗逆转录病毒治疗[HAART] 利托那韦显示出显著的免疫结构， 记忆和幼稚CD 4 T细胞持续增加三到十倍， 细胞亚群 在大多数儿童中， 大于一个对数的病毒负荷伴随免疫重建， 尽管病毒水平很少降低到检测不到。 与此相反， 大约三分之一的儿童对病毒学反应有限， HAART，即使有戏剧性的免疫重建和改善， 临床过程 基因型耐药性在病毒中发展， 在抗病毒治疗期间出现，与病毒负荷的变化无关。 治疗后病毒的其他特征，如嗜性， 表型，复制水平，宿主细胞范围，以及 病毒基因组区域的遗传变异性， 药物的靶向，没有得到很好的研究，特别是在 儿童群体，是提案的重点。 研究计划 旨在检验T细胞重建是 受病毒的影响，这些病毒是对HAART的反应， 与治疗前的病毒性质不同。 有三 具体目标：1. 评估生物学表型和遗传学变化 治疗儿童中出现的M嗜性病毒的复杂性 HAART。 2.确定M嗜性病毒和幼稚病毒之间的相互作用 或记忆性CD 4 T细胞，其与病毒水平相关 在HAART期间。 3. 确定有助于实现以下目标的机制： M嗜性病毒复制能力的显著差异， 用一种新的方法来评估M嗜性病毒之间的相互作用 包膜糖蛋白和趋化因子受体。 研究计划 包括新的方法来评估定量之间的相互作用， 病毒和宿主细胞，以了解体内发病机制。 结果将提供新的参数，除了病毒负荷， 可用于评估出现在 儿童和成人对HAART的反应。 这些因素作为 免疫构成的预测因子对于评估 HAART的疗效，以及旨在 增强免疫功能或提供抗感染保护。

The long-term objective of the proposed research is to understand molecular mechanisms of HIV-1 pathogenesis. Children receiving highly active antiretroviral therapy [HAART] with the protease inhibitor ritonavir display dramatic immunoreconstitution that produces rapid and sustained three- to ten-fold increases in both memory and naive CD4 T cell subsets. In the majority of children a significant reduction of greater then one log in viral burden accompanied immunoreconstitution, although virus levels were seldom reduced to undetectable. In contrast, about one-third of the children had limited virological response to HAART, even with dramatic immune reconstitution and improvement in clinical course. Genotypic drug resistance developed in viruses that emerged during antiviral therapy independent of changes in virus burden. Other characteristics of post therapy viruses, such as tropism, phenotype, levels of replication, host cell range, and dynamics of genetic variability in regions of the virus genome other than those targeted by the drugs, are not well studied, particularly in the pediatric population, and are the focus of the proposal. Research plan is designed to test the hypothesis that T cell reconstitution is influenced by the viruses, which emerge in response to HAART and are qualitatively different from pretherapy viruses. There are three specific aims: 1. To assess changes in biological phenotype and genetic complexity of M-tropic viruses that emerge in children treated with HAART. 2. To identify interactions between M-tropic viruses and naive or memory CD4 T cells in vivo which are associated with virus levels during HAART. 3. To identify mechanisms which contribute to significant differences in replicative ability of M-tropic viruses by using a novel approach to evaluate interactions between M-tropic virus envelope glycoproteins and chemokine receptors. The research plan includes novel approaches to assess quantitative interactions between viruses and host cells to understand mechanisms of pathogenesis in vivo. Results will provide new parameters that, in addition to viral burden, can be used to evaluate pathogenic potential of viruses that emerge in response to HAART in children and in adults. Factors that serve as predictors of immunoreconstitution are important for assessing the efficacy of HAART, as well as the efficacy strategies designed to augment immunoreconstitution or provide protection from infection.