Impact of HIV-1 Genotype on Therapy Response in Children

描述（由申请方提供）：长期目的是检查HIV感染儿童和青少年的HIV演变和免疫功能，这些儿童和青少年在开始含蛋白酶抑制剂的抗逆转录病毒治疗[ART]后重建免疫[免疫成功，IS]但未能控制病毒复制[病毒失败，VF]。研究将集中在一个独特的队列治疗的患者谁持续免疫重建，尽管病毒载量，将预测疾病进展。这个结果组提出了一个新的模式，为调查病毒/宿主细胞的相互作用，可能会导致新的新的治疗策略。该提议的假设是ART诱导的不一致反应是多因素的，涉及病毒的表型特性、胸腺的功能完整性以及正在进行的病毒复制对免疫的影响。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VF/IS个体外周血中Gag和蛋白酶[PR]氨基酸替换的进化动力学。在ART期间在VF/IS个体中形成的Gag和PR氨基酸序列中的遗传标志物的积累和调节将用于评价：[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。鉴定VF/IS个体gag和PR中优先导致胸腺细胞限制性复制的遗传决定因素。将构建具有源自不一致患者的gag/PR区的重组病毒，并在培养物中进行评价，以：[A.]比较来自VF/IS个体的病毒的治疗前和治疗后gag/PR区在胸腺细胞和PBMC中离体复制的能力，和[B.]绘制Gag和PR中有助于胸腺细胞优先限制复制能力的遗传决定因素。 具体目标3。在病毒和免疫结果不一致的个体中，确定持续病毒复制对免疫力的影响。具体研究将评价：[A.]胸腺输出[B.]胸腺T细胞活化和分化后，和[C.] VS/IS和VF/IS结果组之间对新抗原的功能性免疫应答。

DESCRIPTION (provided by applicant): 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.