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

 描述：现在很明显，单靠抗逆转录病毒疗法(ART)并不能根除艾滋病毒：即使在经过15年以上的密集和持续治疗后，除特殊情况外，病毒在停止ART后的几周内都会重新开始传播。一小群潜伏感染的细胞，通常被称为艾滋病毒感染的“蓄水池”，提供了反弹病毒血症的长期来源。诱导HIV表达结合ART已被提出作为一种策略来消除持续感染的细胞，这些细胞最终可能导致病毒根除，然而，目前的方法都没有导致潜在储存库的大小显著减少。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POTET HIV特异性CD8T细胞来消除最近重新激活的潜伏感染的CD4T细胞。事实上，伴随着病毒抗原载量的下降，HIV特异性CD8T细胞在ART启动后迅速消失，在抑制治疗期间仍然几乎检测不到。因此，在个人身上长期实施的震荡和杀戮策略很可能失败。一种根本不同的方法是在ART开始时重新激活先前存在的潜伏库，而HIV特异性CD8 T细胞仍处于高频状态。我们假设，在ART启动期间有一个机会之窗，在那里，重新激活剂的使用将重新激活潜伏感染的CD4T细胞(休克)，并导致HIV特异性CD8T细胞(KILL)对HIV储存库的增强杀伤，因为这些细胞在这个阶段仍然以高频率存在。这项建议的主要目的是提供证据 在SIV模型中的一个概念是，在ART开始时添加再活化剂将由于CD8 T细胞的Pott杀伤而导致潜伏病毒库的大小显著减小。为了实现这一目标，我们将使用Bryostatin-1(BRYO-1)作为基准重新激活剂，因为我们观察到这种PKC激动剂是从病毒抑制的个体中重新激活人类CD4T细胞中潜伏的HIV的最有效的分子。在R21阶段，我们将验证BRYO-1可以作为SIV模型中的基准复活剂，并确定体内使用的最佳剂量。在R33阶段，我们将在非人类灵长类(NHP)模型中测试这一新概念，印度来源的恒河猴感染SIV，特别是表达MHC类1等位基因Mamu-A*01，该等位基因与强大的SIV特异性CD8 T细胞反应相关。我们将比较单独接受ART、ART+延迟BRYO-1和ART+即刻BRYO-1的动物的潜伏库的大小，并证明在ART启动时接受BRYO-1的动物的潜伏库的消除是由CD8 T细胞杀伤介导的。此外，我们将中断这些动物的ART，以确定这一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，在临床试验中，根除药物将与抗逆转录病毒治疗一起使用。

 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.