Persistent Virus Reservoirs in SIV-infected Macaques

描述(申请人提供)：尽管艾滋病研究取得了许多进展，包括有效控制大部分艾滋病毒感染患者病毒复制的有效抗逆转录病毒疗法(ART)，但能够治愈感染的治疗方法仍然难以找到。为此，需要新的方法来根除潜伏感染细胞的储存库，这些细胞在抗逆转录病毒治疗期间持续存在，并在治疗中断时成为病毒重新激活的来源。在这项拨款申请的R21阶段，我们建议使用现有的猕猴SIVmac感染(RMS)的非人类灵长类动物模型，通过开发一个实验系统来验证艾滋病毒根除/功能治愈的研究，在该实验系统中，通过有效的ART方案(目标1)在体内完全和持续地抑制病毒复制。然后，我们将使用这个经过验证的模型来直接在体内和在多个器官中研究潜伏感染细胞持久储存库的解剖和表型性质，特别关注共同抑制分子(即PD-1、CTLA-4、TIM-3和LAG-3)的表达与持久性储存库大小之间的关系(目标2)。本申请的R21部分建议的研究结果将为在本建议的R33阶段进行的进一步实验铺平道路，在该阶段，我们将在完全抑制病毒复制的ART治疗的SIV感染的RMS中测试基于免疫的干预措施，旨在减少并可能消除体内持续存在的潜伏感染细胞。这个 建议的关键干预措施包括阻断与SIV潜伏期最密切相关的共抑制途径，这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)联合进行。我们相信，拟议的研究将为潜伏感染细胞的持续病毒库的生物学提供前所未有的见解，并阐明靶向CO的可能性。 在SIV感染过程中减少宿主的抑制途径。

DESCRIPTION (provided by applicant): Despite many advances in AIDS research, including the availability of potent anti-retroviral therapy (ART) that effectively controls virus replicatio 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 th 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.