Impact of HIV-1 Genotype on Therapy Response in Children

长期目标是检查艾滋病毒感染儿童的艾滋病毒进化和免疫功能，以及 青少年，在开始含有抗逆转录病毒治疗的蛋白酶抑制剂后，重建 免疫[免疫成功，IS]，但未能控制病毒复制[病毒失败，VF]。研究的重点将是 独一无二的接受治疗的患者队列，他们在病毒负载的情况下仍保持免疫重建 预测疾病进展。这一成果小组提出了一种新的研究范式 病毒/宿主细胞的相互作用可能导致新的治疗策略。假说 这一提议的基础是，ART诱导的不和谐反应是多因素的，涉及表型 病毒的特性，胸腺的功能完整性，以及正在进行的病毒复制对 豁免权。为了确定VF/IS响应涉及的机制，提出了三个具体目标： 具体目标1.研究GAG和蛋白酶[PR]中氨基酸替换的进化动力学 在VF/IS个体的外周血室内。基因的积累与调控 在ART期间在VF/IS个体中形成的GAG和PR氨基酸序列中的标记将用于 评估：[A]血浆和CD4、CD45RO、T淋巴细胞和[B]中病毒的区隔。 CD_4、CD_(45)RA T淋巴细胞中的病毒贮存库。 具体目标2.确定VF/IS个体GAG和PR中的遗传决定因素 优先于胸腺细胞中的限制性复制。含有GAG/PR区的重组病毒来源于 不和谐的患者将在培养中被构建和评估：[A]比较治疗前后的情况 VF/IS患者病毒的Gag/PR区与其在胸腺细胞中的复制能力 和PBMC体外和[B]定位在GAG和PR中有助于偏爱的遗传决定因素 胸腺细胞复制能力的限制。 具体目标3.确定正在进行的病毒复制对患有以下疾病的个人免疫的影响 病毒和免疫结果不一致。具体研究将评估：[A]胸腺输出，[B.]胸腺后T细胞 细胞激活和分化，以及[C]。VS/IS和VIS对新抗原的功能性免疫应答 VF/IS结果组。

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.