Nonhuman Primate Core

HIV治愈的一个主要障碍是HIV-1感染细胞的持久性，这些细胞构成了病毒库，甚至 在长期联合抗逆转录病毒治疗(CART)后，如果病毒复制，则会推动持续快速的反弹 在手推车中断之后。不幸的是，即使是在急性期开始接受抗逆转录病毒治疗的患者也是如此。 感染。因此，长期持续的艾滋病毒宿主在感染后迅速播种，我们的团队和其他人 已经在非人类灵长类艾滋病毒模型中证实了这一发现。此外，来自几个小组和 我们的研究有力地表明，残留的病毒复制实际上正在各种淋巴组织中进行，尽管 高度活跃的购物车，无论是由于药物渗透性差、药物代谢不良，还是由于抗病毒药物有限的避难所 免疫贡献。我们正在进行的猿猴免疫缺陷水库调查的初步数据 在感染后不到7天的时间里，用ART感染恒河猴导致了意想不到的发现： 1)我们能够看到SIV在CART启动后1周内扩展并定居整个主机，使用 免疫PET/CT监测，此后信号减弱；2)即使在CART 6-8个月后， 免疫PET/CT能灵敏地检测到组织中残留的病毒(蛋白质)信号，尽管无法检测到 血液中的病毒血症；ART中断后，病毒信号最早在手推车中断后4天反弹 (ATI)，但也是在血浆中检测到病毒的两周前；对组织和细胞的分析 令人惊讶的是，反弹显示T细胞很少，但主要是髓系细胞，在 其中，许多人肥大细胞特异性类胰蛋白酶生物标记物呈阳性。虽然我们的团队已经记录了 在过去，肥大细胞在体外培养对艾滋病毒和SIV感染的敏感性，这是第一次 明确的证据表明，肥大细胞可能至少对很早就播种的SIV储备库做出了贡献。在这 应用，我们建议在CART启动的情况下在6周内量化和绘制储集层形成图 感染后，作为更具代表性的人类临床，采用了一系列最先进的影像引导 收集技术，允许对不同时间获得的水库进行详细的细胞和病毒分析 Cart和早期的ATI。接下来，我们建议解决延长CART后的功能病毒库 在没有免疫干预的情况下，允许瞬时病毒复制，最后，调查 在ATI上对油藏动态和组成进行这种干预，以努力阐明新的战略 为了让未来的病毒者们安静下来

A major barrier to HIV cure is the persistence of HIV-1 infected cells that constitute the viral reservoir which even after prolonged combined antiretroviral therapy (cART), fuels a consistent and rapid rebound if viral replication following cART interruption. This has unfortunately been true even for patients initiated on ART during acute infection. Thus, long-term persistent HIV reservoirs are seeded rapidly post infection, and our team and others have confirmed this finding in the nonhuman primate model of HIV. In addition, data from several groups and ours strongly suggest that residual viral replication is actually ongoing in various lymphoid tissues in spite of highly active cART, be it due to poor drug penetration, drug metabolization, or sanctuaries with limited antiviral immune contribution. Preliminary data from our ongoing reservoir investigations in the simian immunodeficiency infection of rhesus macaques with ART initiated less than 7 days post infection have led to unexpected findings: 1) we were able to see SIV expand and colonize the entire host for >1 week post cART initiation using immunoPET/CT monitoring, with signal decreasing thereafter; 2) Even after 6-8 months of cART, immunoPET/CT was sensitive enough to detect residual viral (protein) signal in tissues in spite of undetectable viremia in the blood; upon ART interruption, viral signals rebounded as early as 4 days post cART interruption (ATI) but also 2 weeks before detection of virus in plasma; analysis of the tissues and cells fueling this initial rebound surprisingly showed a paucity if not absence of T cells, but predominantly myeloid type cells, among which, many appeared positive for the mast cell specific tryptase biomarker. While our team had documented the ability of developing mast cells to be susceptible to HIV and SIV infection in vitro in the past, this was the first clear evidence that mast cells may contribute at the very least to the very early seeded SIV reservoir. In this application, we propose to quantify and map the reservoir formation in the context of cART initiation at 6 weeks post infection, as more representative of the human clinic, using a series of state of the art imaging guided collection techniques allowing for detailed cellular and viral analyses of the reservoirs obtained at various times of cART and early ATI. Next we propose to address the functional viral reservoir following prolonged cART with and without immune interventions designed to allow for transient viral replication, and finally, investigate the role of such interventions on the reservoir dynamic and composition upon ATI, in efforts to articulate novel strategies to silence viral reservoirs in the future