Persistent Virus Reservoirs in SIV-infected Macaques

摘要 尽管艾滋病研究取得了许多进展，包括可获得有效的抗逆转录病毒疗法 (ART)有效控制很大比例艾滋病毒感染患者的病毒复制，这是一种治疗方法 能够治愈感染的方法仍然难以捉摸。为此，需要新的方法来根除 在抗逆转录病毒治疗期间持续存在的潜伏感染细胞的蓄水池，当病毒在以下情况下重新激活时 治疗被打断了。 在这项赠款申请的R21阶段，我们建议使用现有的、成熟的非人类 恒河猴SIVmac感染灵长类动物模型(RMS)验证HIV研究 通过开发一种实验系统来根除/功能治愈，在该系统中，病毒复制完全和 在体内被有效的ART方案持续抑制(目标1)。然后我们将使用此经过验证的 模型直接在体内和在多个器官中研究动物的解剖和表型性质 潜伏感染细胞的持久性蓄水池，特别关注 共抑制分子(即PD-1、CTLA-4、TIM-3和LAG-3)的表达和持久性的大小 水库(目标2)。在本申请的R21部分中建议的研究结果将为 进一步试验的方式，将在本提案的R33阶段进行，在该阶段中，我们将在 ART治疗的SIV感染的RMS完全抑制病毒复制，基于免疫的干预 旨在减少并可能在体内消除潜伏感染细胞的持续蓄水池。这个 建议的关键干预措施包括阻断与最密切相关的共抑制途径 有SIV潜伏期，将作为单独治疗或与非特异性 病毒复活剂(即组蛋白脱氨酶抑制剂SAHA)。 我们相信，拟议的研究将为持久力的生物学提供前所未有的见解。 潜伏感染细胞的病毒库，并阐明靶向共抑制通路的可能性 以减少SIV感染期间的蓄水池。

Abstract Despite many advances in AIDS research, including the availability of potent anti-retroviral therapy (ART) that effectively controls virus replication in a large proportion of HIV-infected patients, a treatment that can cure the infection remains elusive. To this end, new approaches are required to eradicate the reservoirs of latently infected cells that persist during ART and are the source of virus reactivation when therapy is interrupted. In the R21 phase of this grant application we propose to use the existing, well-established non-human primate model of SIVmac infection of rhesus macaques (RMs) to validate studies of HIV eradication/functional cure by developing an experimental system in which virus replication is fully and persistently suppressed in vivo by a potent ART regimen (Aim #1). We will then use this validated model to investigate directly in vivo and in multiple organs the anatomic and phenotypical nature of the persistent reservoirs of latently infected cells, with specific focus on the relationship between expression of co-inhibitory molecules (i.e., PD-1, CTLA-4, TIM-3, and LAG-3) and size of the persistent reservoirs (Aim #2). The results of the studies proposed in the R21 part of this application will pave the way for further experiments, to be conducted in the R33 phase of this proposal, in which we will test, in ART-treated SIV-infected RMs with full suppression of virus replication, immune-based interventions aimed at reducing and possibly eliminating in vivo the persisting reservoirs of latently infected cells. The key proposed intervention consists of a blockade of the co-inhibitory pathway most closely associated with SIV latency, which will be performed as a stand-alone therapy or in combination with a non-specific virus reactivating agent (i.e., the histone deacytelase inhibitor, SAHA). We believe that the proposed studies will provide unprecedented insights into the biology of persistent virus reservoirs of latently infected cells, and elucidate the potential of targeting co-inhibitory pathways to reduce the reservoir during SIV infection.