Targeting the Persistent HIV-1 Viral Reservoir Using Engineered T cells

描述(由申请人提供)：持久的、潜伏的病毒库仍然是根除艾滋病毒-1的一个重大障碍。最近，已经有了一些突破，现在为如何严重减少或消除这种艾滋病毒-1宿主提供了路线图。与这一应用最相关的是，Siliciano实验室最近报告说，一旦HDAC抑制诱导HIV-1基因表达，就需要CTL活性来减少潜伏库。在这笔赠款的R21部分，我们将评估几种药物在没有毒性或T细胞激活的情况下诱导HIV-1基因表达的能力。我们假设HDAC6抑制剂将特别有效，因为HDAC有效地对抗HIVTAT活性。接下来，作为一系列高风险、高回报的实验，我们将设计T细胞，以高亲和力和特异性识别HIV-1ENV或HIV-1GAG，并使用几种经过验证的体外潜伏期分析来询问这两种工程T细胞是否可以减少潜伏期。如果我们的R21部分赠款的结果是成功的，然后我们将进入R33阶段，在此阶段，我们测试工程T细胞减少良好控制HAART患者HIV-1宿主的能力~测试作为独立治疗的增强亲和力TCR控制患者HIV-1宿主的能力，并使用最近描述的人源化潜伏期小鼠模型评估工程T细胞靶向体内潜在宿主的能力。

DESCRIPTION (provided by applicant): The persistent, latent viral reservoir remains a significant barrier to the eradication of HIV-1. Recently, there have been a number of breakthroughs that now give a roadmap on how to severely reduce or eliminate this HIV-1 reservoir. Of most relevance to this application, the Siliciano Lab recently reported that CTL activity is required to reduce the latent reservoir once HIV-1 gene expression induced by HDAC inhibition. In the R21 portion of this grant, we will evaluate the ability of several agents to induce HIV-1 gene expression in the absence of toxicity or T cell activation. We hypothesize that HDAC6 inhibitors will be especially potent as HDAC potently opposes HIVTAT activity. Next, as a high risk, high reward series of experiments we will engineer T cells to recognize HIV-1ENV or HIV-1GAG with high affinity and specificity and ask if either of these engineered T cells can reduce the latent reservoir using several validated in vitro latency assays. If our results from the R21 portion of the grant are successful, we will then move into the R33 phase in which we test the ability of engineered T cells to reduce the HIV-1 reservoir in well controlle HAART patients~ test the ability of enhanced affinity TCRs to control the HIV-1 reservoir in patients as a standalone treatment and evaluate the ability of engineered T cells to target the latent reservoir in vivo using a recently described humanized mouse model of latency.