Targeting HIV-1 persistence with Interferon-a

 描述：HIV-1会导致一种慢性感染，需要长期服用抑制性抗逆转录病毒药物，但目前可用的干预措施无法治愈。HIV-1治愈的最主要障碍是潜伏感染的CD4T细胞，在这些细胞中，HIV-1保持转录沉默，不受传统抗逆转录病毒药物的影响。这个 开发干预策略，减少潜伏感染细胞的数量，并在停止治疗后延缓病毒反弹，将对许多艾滋病毒-1患者有实质性好处。这项建议旨在通过重点研究干扰素-的作用来探索治愈/根除艾滋病毒-1的干预措施，干扰素-干扰素是一种有效治疗慢性丙型肝炎病毒感染的免疫调节剂。多年来，人们已经认识到，干扰素-可以有效地将未经治疗的患者的艾滋病毒-1病毒载量降低约1log，这表明它在体内对主动复制的艾滋病毒-1具有强大的活性，但干扰素-对潜伏的艾滋病毒-1的作用 被感染的细胞目前仍不清楚。这一应用的中心假设是，除了对主动复制艾滋病毒-1的作用外，干扰素-还可以对潜伏感染的艾滋病毒-1细胞发挥强大的活性，并且这些作用是由于先天、细胞固有和获得性免疫机制的组合。为了研究这一点，我们将集中在大量接受干扰素-/利巴韦林治疗的HIV-1感染患者中，他们接受丙型肝炎病毒感染的治疗，并纵向收集大量的PBMC进行免疫学、病毒学和免疫遗传学研究。在最初的步骤中，我们将使用这些样本来表征艾滋病毒-1感染的CD4T细胞亚群的储存库，以及在干扰素-治疗期间携带复制能力艾滋病毒-1的艾滋病毒-1感染细胞的数量(特定目标1，R21阶段)。使用相同患者的样本，我们随后将评估与HAART期间HIV-1 CD4 T细胞库减少(特异性目标2，R33阶段)以及与减少HIV感染细胞库相关的先天和适应性效应细胞反应(特异性目标3，R33阶段)相关的免疫遗传学特征。随后，接受干扰素-治疗的艾滋病毒-1患者的样本和艾滋病毒-1潜伏期的体外模型将被用来从机械上分析从病毒潜伏期重新激活如何诱导细胞应激反应，从而增加细胞对天然和适应性效应细胞免疫介导的清除的敏感性(特异性目标4，R33阶段)，并研究CD4T细胞中可能选择性地导致细胞死亡和凋亡的细胞内在免疫识别(特异性目标5，R33阶段)。因此，拟议项目的主要成果将是在干扰素-治疗HAART治疗的艾滋病毒-1患者过程中发生的病毒学和免疫学变化的综合、全面的数据集，以及对在干扰素-治疗期间有助于减少病毒库的免疫机制的更好理解；这些数据将为设计未来根除艾滋病毒-1的临床试验提供非常有用的信息。

 DESCRIPTION: HIV-1 leads to a chronic infection that requires long-term administration of suppressive antiretroviral agents, but cannot be cured with currently available interventions. The most dominant barrier against a cure of HIV-1 consists of latently-infected CD4 T cells in which HIV-1 remains transcriptionally silent, and is unaffected by traditional antiretroviral agents. The development of interventional strategies that can reduce the number of latently infected cells and delay viral rebound after treatment discontinuation would be of substantial benefit for many HIV-1 patients. This proposal sets out to explore interventions for curing/eradicating HIV-1 by focusing on effects of IFN- an immunomodulatory agent that is effective in curing chronic HCV infection. For many years, it has been recognized that IFN- can effectively reduce HIV-1 viral loads in otherwise untreated patients by approximately one log, indicating that it has potent in vivo activities against actively-replicating HIV- 1, but the role of IFN- against latently HIV-1 infected cells remains currently unknown. The central hypothesis of this application is that in addition to its effects on actively replicating HIV-1, IFN- can also exert potent activities aganst the reservoir of latently infected HIV-1 cells, and that these effects are due to a combination of innate, cell-intrinsic and adaptive immune mechanisms. To investigate this, we will focus on a large cohort of HAART-treated HIV-1 infected patients who underwent treatment with IFN- /Ribavirin (RBV) for treatment of Hepatitis C infection, and from whom large number of PBMC were longitudinally collected for immunologic, virologic and immunogenetic studies. In an initial step, we will use these samples to characterize the reservoir of HIV-1 infected CD4 T cell subsets, and the number of HIV-1 infected cells harboring replication-competent HIV-1 during treatment with IFN- (specific aim 1, R21 phase). Using samples from the same patients, we will subsequently evaluate immunogenetic characteristics associated with reduction of the HIV-1 CD4 T cell reservoir (specific aim 2, R33 phase) and innate and adaptive effector cell responses (specific aim 3, R33 phase) associated with a reduction of the reservoir of HIV-infected cells during HAART. Subsequently, samples from HIV-1 patients receiving IFN- and in vitro models of HIV-1 latency will be used to mechanistically analyze how reactivation from viral latency may induce a cellular stress response that increases cellular susceptibility to immune-mediated clearance by innate and adaptive effector cells (specific aim 4, R33 phase), and to investigate cell-intrinsic immune recognition in CD4 T cells that may selectively lead to cell death and apoptosis in cells in which reactivation occurs (specific aim 5, R33 phase). As such, the major deliverable of the proposed project will be an integrated, comprehensive dataset of virologic and immunologic changes occurring during IFN- treatment of HAART-treated HIV-1 patients, and an improved understanding of immune mechanisms contributing to reduction of the viral reservoir during IFN- treatment; these data will be very informative for designing future clinicl trials for HIV-1 eradication.