HIV latency reversal through novel, potent PKC modulators

 描述(申请人提供)：虽然抗逆转录病毒疗法(ART)在阻止或减缓大多数艾滋病毒感染者的疾病进展方面是有效的，但它不是治愈的。相反，抗逆转录病毒治疗必须是终生持续的，需要严格遵守，费用高昂，并与许多健康问题有关，可归因于长期的化疗暴露。根除病毒将解决这些问题，然而，事实证明，这是极其困难的。减少或消除艾滋病毒宿主的一种潜在方法是在接受抗逆转录病毒治疗时给药，将病毒从隐藏的地方冲洗出来，这应该会通过病毒介导的细胞毒性或免疫介导的清除来诱导细胞死亡。或者，可以使用针对新表达的病毒抗原的额外试剂来完成这一“先踢后杀”策略。蛋白激酶C(PKC)调节剂是迄今为止发现的最有效的HIV潜伏期逆转药物之一。然而，天然的PKC调节剂具有固有的毒性和次佳的效力。这项建议汇集了几个在化学、病毒学和动物模型方面具有相关专业知识的实验室，通过一套临床前评估来推进合成PKC调节剂的研究，以减少毒性并改善潜伏期逆转活动。我们将扩大合成几种(已经确定的)改进的PKC调节剂，并创造这些化合物的新的缓释版本，有可能进一步降低毒性。我们将让这些分子在包括抑制ART患者的原代细胞在内的各种测试中进行体外活性评估，并在人源化小鼠中进行潜伏期逆转的体内建模。这反过来将为拟议的非人类灵长类动物的药理学和疗效研究提供信息。总之，这里提出的研究将提供关于根除艾滋病毒的踢杀方法的重要信息，并将这些独特和优越的化合物推向临床试验。

 DESCRIPTION (provided by applicant): While antiretroviral therapy (ART) has been effective in stopping or slowing disease progression for most HIV infected individuals, it is not curative. ART must instead be continuous for life, requires strict compliance, is costly, and is implicated i numerous health problems attributed to long-term chemo-exposure. Eradication of the virus would address these problems, however this has proven extremely difficult. One potential means of reducing or eliminating HIV reservoirs is to administer agents to flush the virus out of hiding while on ART, which should induce death of the cell either by virus-mediated cytotoxicity, or immune-mediated clearance. Alternatively, additional reagents specific for newly expressed viral antigens could be administered to complete this "kick and kill" strategy. Protein kinase C (PKC) modulators are among the most active HIV latency reversing agents identified to date. However, natural PKC modulators have inherent toxicities and sub-optimal potencies. This proposal brings together several laboratories with relevant expertise in chemistry, virology and animal modeling, to advance the study of synthetic PKC modulators with reduced toxicities and improved latency reversal activities through a suite of pre-clinical assessments. We will scale-up synthesis of several (already identified) improved PKC modulators, and create novel slow release versions of these compounds with the potential to further reduce toxicities. We will subject these molecules to in vitro assessment of activity in various assays including primary cells from patients on suppressive ART, and perform in vivo modeling of latency reversal in humanized mice. This in turn will inform proposed pharmacology and efficacy studies in non-human primates. Together the studies proposed herein will provide important information regarding kick and kill approaches for HIV eradication, and advance these unique and superior compounds towards clinical testing.