Purging the latent HIV reservoir at ART inititation: A new eradication strategy

在 ART 启动时清除潜伏的 HIV 病毒库：新的根除策略

• 批准号: 9060627
• 负责人: Nicolas Chomont
• 金额: $ 24.89万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060627
• 关键词: Agonist; Alleles; Animals; Benchmarking; Biological; Biological Assay; Biological Markers; Blood specimen; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Clinical; Clinical Trials; Collaborations; Control Groups; Development; Dose; Frequencies; HIV; HIV Infections; Health; Human; In Vitro; Individual; Infection; Interruption; Lead; Life; Macaca; Macaca mulatta; Measures; Mediating; Modeling; Oregon; Pathway interactions; Pharmaceutical Preparations; Phase; Pilot Projects; Protein Kinase C; Regimen; Residual state; Role; SIV; Shock; Source; Staging; T cell response; T-Lymphocyte; Testing; Time; Tissue Sample; Toxic effect; Viral; Viral Antigens; Viremia; Virus; antiretroviral therapy; base; bryostatin; cell killing; cytokine; in vivo; killings; nonhuman primate; novel strategies; purge; success

 DESCRIPTION: It is now clear that antiretroviral therapy (ART) alone does not eradicate HIV: Even after more than 15 years of intensive and continuous therapy, the spread of the virus resumes within a few weeks upon cessation of ART in all but exceptional cases. A small pool of latently infected cells, usually referred as the "reservoir" of HIV infection, provides a long-live source of rebound viremia. Inducing HIV expression combined with ART has been proposed as a strategy to eliminate persistently infected cells that could ultimately lead to viral eradication However, none of the current approaches has led to a significant decrease in the size of the latent reservoir. A likely explanation for these disappointing results is given by the lack of potet HIV specific CD8 T cells to eliminate the recently reactivated latently infected CD4 T cells in virally suppressed subjects. Indeed, concomitant to the decrease in viral antigen load, HIV-specific CD8 T cells rapidly vanish after ART initiation and remain barely detectable during suppressive therapy. Therefore, shock and kill strategies implemented in individuals on long-term ART are likely to fail. A fundamentally different approach is to reactivate the pre-existing latent reservoir when ART is started while HIV-specific CD8 T cells are still at high frequencies. We hypothesize that there is a window of opportunity during ART initiation where the use of a reactivating agent would reactivate latently-infected CD4 T cells (shock) and lead to an enhanced killing of the HIV reservoir by HIV-specific CD8 T cells (kill), as these cells are still present at high frequency at this stage. The major objective of this proposal is to provide a proof of concept in the SIV model that the addition of a reactivating agent administered at ART initiation will lead to a significant decrease in the size of the latent viral reservoir due to potnt killing by CD8 T cells. To achieve this objective, we will use bryostatin-1 (BRYO-1) as a benchmark reactivating agent since we have observed that this PKC agonist is the most potent molecule to reactivate latent HIV in human CD4 T cells from virally suppressed individuals. In the R21 phase, we will validate that BRYO-1 can be used as benchmark reactivating agent in the SIV model and determine the optimal dose to be used in vivo. During the R33 phase, we will test this new concept in the non-human primate (NHP) model of HIV, SIV infection of Indian origin rhesus macaques specifically selected for expressing the MHC class 1 allele Mamu-A*01, that has been associated with potent SIV-specific CD8 T cell responses. We will compare the size of the latent reservoir in animals that will receive ART alone, ART + delayed BRYO-1 and ART + immediate BRYO-1 and demonstrate that the elimination of latent reservoir in animals receiving BRYO- 1 at ART initiation is mediated by CD8 T cell killing. In addition, we will interrupt ART in these animals to determine the potential clinical benefit of this novel strategy aimed at achieving a functional cure. This study will pave the way to the rapid development of clinical trials in which an eradication agent will be administered together with ART.

 描述：现在很清楚，单独的抗逆转录病毒治疗 (ART) 并不能根除 HIV：即使经过超过 15 年的强化和连续治疗，除了特殊情况外，在停止 ART 后的几周内，病毒的传播仍然会恢复。一小群潜伏感染的细胞，通常被称为艾滋病毒感染的“储存库”，提供了病毒血症反弹的长期来源。诱导HIV表达与ART相结合已被提议作为消除持续感染细胞的策略，最终可能导致病毒根除。然而，目前的方法都没有导致潜伏病毒库大小的显着减小。对这些令人失望的结果的一个可能的解释是，在病毒抑制的受试者中，缺乏有效的 HIV 特异性 CD8 T 细胞来消除最近重新激活的潜伏感染的 CD4 T 细胞。事实上，随着病毒抗原载量的减少，HIV 特异性 CD8 T 细胞在 ART 开始后迅速消失，并且在抑制治疗期间几乎检测不到。因此，对接受长期抗逆转录病毒疗法的个体实施的休克和杀戮策略很可能会失败。一种根本不同的方法是在 ART 开始时重新激活预先存在的潜在储存库，同时 HIV 特异性 CD8 T 细胞仍处于高频率。我们假设，在 ART 启动期间存在一个机会窗口，其中使用重新激活剂将重新激活潜伏感染的 CD4 T 细胞（休克），并导致 HIV 特异性 CD8 T 细胞增强对 HIV 储存库的杀伤（杀死），因为这些细胞在此阶段仍以高频率存在。该提案的主要目的是提供证据 SIV 模型中的概念是，在 ART 开始时添加重新激活剂，由于 CD8 T 细胞的有效杀伤作用，将导致潜伏病毒库的大小显着减小。为了实现这一目标，我们将使用苔藓抑素-1 (BRYO-1) 作为基准重新激活剂，因为我们观察到这种 PKC 激动剂是重新激活病毒抑制个体的人类 CD4 T 细胞中潜伏 HIV 的最有效分子。在R21阶段，我们将验证BRYO-1可以作为SIV模型中的基准再激活剂，并确定体内使用的最佳剂量。在 R33 阶段，我们将在 HIV、SIV 感染的非人灵长类动物 (NHP) 模型中测试这一新概念，这些模型是专门选择表达 MHC 1 类等位基因 Mamu-A*01 的印度恒河猴，该基因与有效的 SIV 特异性 CD8 T 细胞反应相关。我们将比较仅接受 ART、ART + 延迟 BRYO-1 和 ART + 立即 BRYO-1 的动物中潜伏病毒库的大小，并证明在 ART 开始时接受 BRYO-1 的动物中潜伏病毒库的消除是由 CD8 T 细胞杀伤介导的。此外，我们将中断这些动物的 ART，以确定这种旨在实现功能性治愈的新策略的潜在临床益处。这项研究将为临床试验的快速发展铺平道路，其中根除剂将与 ART 一起使用。