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HIV感染患者病毒复制的强效抗逆转录病毒疗法（ART）的可用性，但治愈感染的治疗方法仍然难以捉摸。为此，需要新的方法来根除在ART期间持续存在的潜伏感染细胞的储库，并且当治疗中断时，这些储库是病毒再活化的来源。在该资助申请的R21阶段，我们建议使用现有的、完善的恒河猴（RM）SIVmac感染的非人灵长类动物模型，通过开发一种实验系统来验证HIV根除/功能性治愈的研究，在该系统中，病毒复制在体内被有效的ART方案完全和持续抑制（目标1）。然后，我们将使用该经验证的模型直接在体内和多个器官中研究潜伏感染细胞的持久性储库的解剖学和表型性质，特别关注共抑制分子（即PD-1，CTLA-4，TIM-3和LAG-3）的表达与持久性储库大小之间的关系（目的2）。在本申请的R21部分中提出的研究结果将为在本申请的R33阶段中进行的进一步实验铺平道路，其中我们将在ART治疗的SIV感染的RM中测试完全抑制病毒复制的基于免疫的干预措施，旨在减少并可能消除体内潜伏感染细胞的持续储库。的 关键的干预措施包括阻断与SIV潜伏期最密切相关的共抑制途径，这将作为独立治疗或与非特异性病毒再活化剂（即组蛋白脱乙酰酶抑制剂，SAHA）联合使用。我们相信，这些研究将为潜伏感染细胞的持久性病毒库的生物学提供前所未有的见解，并阐明靶向细胞的潜力。 抑制途径以减少SIV感染期间的储库。

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.