Impact of HIV-1 Genotype on Therapy Response in Children

长期目标是研究艾滋病毒感染儿童的艾滋病毒演变和免疫功能， 在开始含蛋白酶抑制剂的抗逆转录病毒治疗[ART]后， 免疫[免疫成功，IS]但不能控制病毒复制[病毒失败，VF]。研究将集中在一个 一个独特的接受治疗的患者队列，尽管病毒载量会 预测疾病进展。这一结果组提出了一个新的范式的调查， 病毒/宿主细胞相互作用，可能导致新的新的治疗策略。的假设 该建议的基础是ART诱导的不一致反应是多因素的，涉及表型 病毒的性质，胸腺的功能完整性，以及正在进行的病毒复制对 免疫力为了确定VF/IS反应所涉及的机制，提出了三个具体目标： 具体目标1。研究Gag和蛋白酶[PR]中氨基酸取代的进化动力学 在VF/IS个体的外周血室中。基因的积累和调节 ART期间VF/IS个体中产生的Gag和PR氨基酸序列中的标记物将用于 评价：[A.]血浆和CD 4 CD 45 RO T淋巴细胞中病毒的区室化和[B.] CD 4CD 45 RA T淋巴细胞中的病毒库。 具体目标2。确定VF/IS个体中gag和PR的遗传决定因素， 优先于胸腺细胞中的限制性复制。具有源自以下的gag/PR区的重组病毒： 将在培养物中构建和评价不一致患者，以：[A.]治疗前后比较 来自VF/IS个体的病毒的gag/PR区域关于它们在胸腺细胞中复制的能力 和PBMC离体和[B.]在Gag和PR中绘制遗传决定因素， 胸腺细胞复制能力的限制。 具体目标3。为了确定持续病毒复制对有免疫缺陷的个体的免疫力的影响， 病毒和免疫结果不一致。具体研究将评价：[A.]胸腺输出[B.]胸腺后T 细胞活化和分化，以及[C.] VS/IS和VS/IS之间对新抗原的功能性免疫应答 VF/IS结局组。

The long-term objective is to examine HIV evolution and immune function in HIV-infected children and adolescents who, following initiation of protease inhibitor containing antiretroviral therapy [ART], reconstitute immunity [Immune success, IS] but fail to control viral replication [viral failure, VF]. Studies will focus on a unique cohort of treated patients who have sustained immune reconstitution in spite of viral loads that would predict disease progression. This outcome group presents a novel paradigm for the investigation of virus/host cell interactions that are likely to lead to novel new therapeutic strategies. The hypothesis underlying the proposal is that ART-induced discordant responses is multifactorial, involving phenotypic properties of the virus, functional integrity of the thymus, and the impact of ongoing viral replication on immunity. To determine the mechanisms involved in VF/IS responses, three specific aims are proposed: Specific Aim 1. To examine the evolutionary dynamics of amino acid substitutions in Gag and protease [PR] within the peripheral blood compartments of VF/IS individuals. Accumulation and modulation of genetic markers in Gag and PR amino acid sequences that develop in VF/IS individual during ART will be used to evaluate: [A.] compartmentalization of viruses in plasma and in CD4 CD45RO T lymphocytes and [B.] reservoirs of virus in CD4 CD45RA T lymphocytes. Specific Aim 2. To identify genetic determinants in gag and PR from VF/IS individuals that contribute preferentially to restricted replication in thymocytes. Recombinant viruses with gag/PR regions derived from discordant patients will be constructed and evaluated in culture to: [A.] compare pre- and post therapy gag/PR regions from viruses from VF/IS individuals with respect to their capacity to replicate in thymocytes and PBMC ex vivo and [B.]map genetic determinants in Gag and PR that contribute to preferential restriction of replicative capacity in thymocytes. Specific Aim 3. To determine the impact of ongoing viral replication on immunity among individuals who have discordant viral and immune outcomes. Specific studies will evaluate: [A.] thymic output, [B.] post thymic T cell activation and differentiation, and [C.] functional immune response to neoantigen between VS/IS and VF/IS outcome groups.