Persistent Virus Reservoirs in SIV-infected Macaques

摘要 尽管艾滋病研究取得了许多进展，包括有效的抗逆转录病毒疗法， (ART)有效控制大部分HIV感染者的病毒复制， 能够治愈感染的方法仍然难以捉摸。为此，需要采取新的办法， 在ART期间持续存在的潜伏感染细胞的储存库，并且是病毒再活化的来源， 治疗中断。 在本资助申请的R21阶段，我们建议使用现有的、成熟的非人类 SIVmac感染恒河猴（RM）的灵长类动物模型，以验证HIV研究 根除/功能性治愈，通过开发一种实验系统，其中病毒复制是完全和 在体内被有效的ART方案持续抑制（目的#1）。然后我们将使用此验证 直接在体内和多个器官中研究的解剖和表型的性质， 潜伏感染细胞的持久储存，特别关注 共抑制分子的表达（即，PD-1、CTLA-4、TIM-3和LAG-3）和持久性巨噬细胞的大小。 （目标#2）。本申请的R21部分中提出的研究结果将为 进一步实验的方式，将在本提案的R33阶段进行，我们将在其中测试， ART治疗的SIV感染RM，完全抑制病毒复制，基于免疫的干预 目的是减少并可能消除体内潜伏感染细胞的持续储库。的 一个关键的干预措施包括阻断最密切相关的共抑制途径， SIV潜伏期，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）。 我们相信，拟议的研究将提供前所未有的深入了解生物学的持久性 潜伏感染细胞的病毒库，并阐明靶向共抑制途径的潜力 以减少SIV感染时的储库。

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.