Dissecting Early Virus Reservoirs in Tissues

霍普实验室最近公布了最早被感染的细胞的鉴定和特征 阴道和直肠接种后48小时取粘膜标本进行SIV检测。在开发这个系统的过程中，希望 实验室已经开发出关键的方法和专业知识，使SIV和免疫靶细胞的研究成为可能 粘膜屏障内的种群。这些能力将与以下战略一起利用： 特别是在组织中的种子感染，因此潜伏的储存库将在这些 粘膜部位(和其他身体部位)。可以验证储集层的特定播种并 辅以弗朗索瓦·维林格开创的独特的PET/CT成像专业知识/基础设施，以检测 活动性病毒感染的焦点。有了粘膜储存库定位的知识，我们还将追踪SIV 从早期储藏细胞的潜伏期反弹，当它级联为病毒血症时，早期抑制性ART 撤回。这些早期事件的识别将由生物发光报告病毒和整体 动物PET/CT。这些方法将为潜伏感染细胞提供关键的新见解，并促进 开发一种治疗艾滋病毒感染的方法。建议的研究将会达致以下具体目标：(1) 定义和描述粘膜病毒库细胞(含有持续/潜伏的SIV的细胞 在压抑的艺术期间)。这将专门描述已建立的具有持久性病毒的细胞的特征 在猕猴急性SIV感染的早期阶段。这一目标将决定表型， 位置、病毒产生状态和粘膜内的持久性 在开始抑制艺术之前，感染的第一天。(2)定义和描述病毒在 停止后，在SIV感染细胞的粘膜病灶之外，并从其产生反弹病毒血症 早期压抑的艺术。该目标使用PET/CT和报告病毒，并将评估主机 反应和生物标志物。(3)确定粘膜储存库随时间的稳定性，并评估 催化mTOR抑制剂(停用ART前和停药后暂时给药)对SIV病毒血症的影响 从粘膜反弹，在ART抑制病毒24周后，最初几天就开始了 SIV的粘膜接种。我们将利用最近发展的方法和专业知识来观察形成 在病毒感染后的最初几天内形成的粘膜蓄水池。通过在特定的水库中播种 我们应该能够观察到从延迟中反弹的区域。更好地了解本地化和 细胞类型的储藏细胞将有助于开发治疗艾滋病毒的药物。

The Hope laboratory has recently published the identification and characterization of the earliest cells infected by SIV in the mucosa 48 hours after vaginal and rectal inoculation. In developing this system, the Hope laboratory has developed critical methods and expertise allowing the study of SIV and immune target cell populations within the mucosal barriers. These capabilities will be leveraged along with a strategy to specifically seed infection in tissue so that the latent reservoir will be generated within a discrete area at these mucosal sites (and other body sites). The specific seeding of the reservoir can be validated and complemented by the unique PET/CT imaging expertise/infrastructure pioneered by Francois Villinger to detect foci of active virus infection. With the knowledge of mucosal reservoir localization, we will also track SIV rebound from latency in the early reservoir cells as it cascades to viremia when early, suppressive ART is withdrawn. Identification of these early events will be aided by bioluminescent reporter viruses and whole animal PET/CT. These approaches will provide critical new insights into latently infected cells and facilitate the development of a cure to HIV infection. The proposed studies will achieve the following specific aims: (1) Define and characterize the mucosal virus reservoir cells (cells harboring SIV that remain persistent/latent during suppressive ART). This will specifically characterize the cells with persistent virus that are established during the earliest aspects of acute SIV infection of macaques. This aim will determine the phenotypes, locations, viral production status, and persistence within the mucosa of these reservoirs established with the first days of infection before starting suppressive ART. (2) Define and characterize the spread of virus within and beyond the mucosal foci of SIV infected cells, and from which rebound viremia originates, after stopping early, suppressive ART. This aim uses using both PET/CT and reporter viruses, and will also evaluate host responses and biomarkers. (3) Determine the stability of the mucosal reservoir over time and evaluate the effects of catalytic mTOR inhibitors (given before and temporarily after stopping ART) on the SIV viremia rebound from mucosa, following 24 weeks of viral suppression by ART that started in the first days after mucosal inoculation of SIV. We will utilize recently developed methods and expertise to observe the formation of the mucosal reservoir formed in the first few days after virus acquisition. By seeding the reservoir in specific areas we should be able to observe the rebound from latency. A better understanding of the localization and cell type of the reservoir cells will facilitate the development of a cure for HIV.