A Pilot Clinical Trial for HIV-1 Eradication

 描述(申请人提供)：尽管目前现有的抗逆转录病毒药物可以有效地抑制艾滋病毒-1的复制，但感染艾滋病毒-1仍然是无法治愈的。这主要与HIV-1建立潜伏的HIV-1感染宿主的能力有关 对目前可用的抗逆转录病毒药物无反应的CD4T细胞。药物重新激活潜伏感染细胞中活跃的HIV-1基因表达可导致细胞病变或免疫介导的清除，是针对潜伏感染细胞的最有前途和最先进的策略之一。与申请者合作进行的先前试点临床试验的结果表明，有效的组蛋白去乙酰酶抑制剂(HDACi)Panobinostat在体内有效地逆转HIV-1潜伏期和瞬时增加血浆HIV-1 RNA。此外，这项工作表明，潘诺比妥的病毒再激活导致部分患者的CD4T细胞相关的HIV-1DNA减少了3-4倍，这种减少与分析治疗中断期间延迟的病毒反弹动力学有关。有趣的是，对免疫参数的详细分析显示，在Panobinostat治疗期间，HIV-1DNA的下降与HIV-1特异性CD8 T细胞的数量或广度无关，而与激活的先天效应细胞的比例密切相关，如NK细胞和浆细胞样树突状细胞。综上所述，这些数据表明，HDACi可以有效地用作潜伏期反转剂，并且当药物诱导病毒重新激活时，先天效应细胞免疫反应对于减少潜伏感染细胞的储备库至关重要。该项目着手将这些观察结果整合到一个概念上的新的艾滋病毒-1根除战略中，该战略基于潘诺比坦作为潜伏期反转剂和聚乙二醇化的IFNA-2a作为先天免疫激活剂的治疗。我们假设，这两种药物的联合使用导致了对潜伏感染细胞的先天免疫依赖性消除，在这些细胞中，病毒的重新激活是由药物诱导的。具体目标(SA)1将侧重于进行一项试点临床试验，在该试验中，30名接受抗逆转录病毒治疗的艾滋病毒-1患者将被随机分成2：1组，在四个为期一周的周期中接受Panobinostat和PEG-IFNA-2a的治疗，每个周期以三周的观察期分隔，或者单独使用Panobinostat治疗四个周期。在SA 2中，我们将研究联合治疗方案如何影响CD4T细胞相关的HIV-1RNA、血浆RNA、HIV-1DNA水平和携带有复制能力的HIV-1的细胞的频率。SA 3旨在综合分析与病毒库大小减少相关的免疫效应，使用一种新的高通量质谱学方法，结合基因表达谱和功能分析。这项研究代表了在艾滋病毒-1病毒学、免疫学、药理学和临床患者护理方面具有互补专业知识的研究人员的跨学科合作，并将为制定旨在根除艾滋病毒-1的临床战略提供高度信息。

 DESCRIPTION (provided by applicant): Although HIV-1 replication can be effectively suppressed with currently existing antiretroviral drugs, infection with HIV-1 remains incurable. This is primarily related to the ability of HIV-1 to establish a latent reservoir of HIV-1-infected CD4 T cells that is unresponsive to currently available antiretroviral agents. Pharmacological reactivation of active HIV-1 gene expression in latently infected cells can result in cellular deat due to cytopathic effects or immune mediated clearance, and represents one of the most promising and most clinically advanced strategies to target latently infected cells. Results from prior pilot clinical trials, conducted in collaboration with the applicants, demonstrate that the potent histone deacetylase inhibitor (HDACi) panobinostat is effective in reversing HIV-1 latency and transiently increasing plasma HIV-1 RNA in vivo. In addition, this work indicated that viral reactivation with panobinostat resulted in a 3-4 fold reduction of CD4 T cell-associated HIV-1 DNA in a subset of patients, and that this decrease was associated with delayed viral rebound kinetics during an analytical treatment interruption. Interestingly, a detailed analysis of immune parameters revealed that decrease of HIV-1 DNA during panobinostat treatment was unrelated to the magnitude or breadth of HIV-1-specific CD8 T cells, but instead strongly correlated to the proportion of activated innate effector cells, such as NK cells and plasmacytoid dendritic cells. Together, these data suggest that HDACi can be used effectively as latency-reversing agents, and that innate effector cell immune responses are critical for reducing the reservoir of latently infected cells when viral reactivation is pharmacologically induced. This project sets out to integrate these observations into a conceptually novel HIV- 1 eradication strategy that is based on treatment with panobinostat as a latency-reversing agent in combination with pegylated IFNa-2a as an innate immune activator. We hypothesize that the concomitant use of both agents leads to innate immunity-dependent elimination of latently infected cells in which viral reactivation is pharmacologically induced. Specific aim (SA) 1 will focus on conducting a pilot clinical trial in which n=30 ART-treated HIV-1 patients will be randomized 2:1 to treatment with panobinostat and PEG-IFNa-2a during four one-week cycles, each of them separated by a three-week observation period, or to four cycles of treatment with panobinostat alone. In SA 2, we will investigate how the combined treatment regimen influences CD4 T cell-associated HIV-1 RNA, plasma RNA, HIV-1 DNA levels and the frequency of cells harboring replication-competent HIV-1. SA 3 is designed to comprehensively analyze immune effects associated with decreases in viral reservoir size, using a novel high-throughput mass spectrometry approach in combination with gene expression profiling and functional assays. This study represents an interdisciplinary collaboration of investigators with complementary expertise in HIV-1 virology, immunology, pharmacology and clinical patient care, and will be highly informative for the development of clinical strategies aiming at HIV-1 eradication.