Discovery and Characterization of Latency-Reversing Compounds

 描述(由申请人提供)：在接受抗逆转录病毒治疗(ART)的患者中，潜伏的HIV在静止的中央记忆T细胞(Medics)中的持久性是有很好的文献记载的。正是这种病毒储存库被认为是目前艾滋病毒治疗策略无法治愈感染的主要原因。重新激活潜伏的艾滋病毒，从而清除人的潜伏的艾滋病毒蓄积物的可能性，促使人们寻找艾滋病毒激活剂，但到目前为止，这些努力尚未产生站得住脚的疗法。由于强大的T细胞激活和细胞因子风暴，一项使用重组抗CD3抗体和IL-2来重新激活潜伏的HIV的临床试验被叫停。在没有全球病毒的情况下重新激活病毒 为了避免炎性细胞因子的过度产生，需要激活T细胞；更不用说T细胞增殖导致潜伏的艾滋病毒储存库的扩张。植物是一种丰富的分子来源，能够调节许多人类免疫反应，包括激活负责重新激活潜伏的HIV-1的信号通路。我们已经从药用植物中鉴定出120种能够重新激活潜伏的HIV-1的提取物。在这些提取物中，有相当大一部分被发现不会激活T细胞，因此构成了消除病毒策略的极佳候选者。基于这些结果，我们得出结论，鉴定具有所需质量的选择性小分子HIV激活剂的目标是可能的。更重要的是，对这些新的潜伏期逆转分子的探索将揭示它们可以与临床上探索的药物协同作用的机制，并在没有一般T细胞激活的情况下重新激活HIV。这些植物类药物的作用机制将与已知的潜伏期逆转药物(如蛋白激酶C和T细胞受体激动剂等)的作用机制进行比较。

 DESCRIPTION (provided by applicant): The persistence of latent HIV in quiescent central memory T cells (Tcm) in individuals treated undergoing anti-retroviral therapy (ART) is well documented. It is this reservoir of virus that is thought to be the principal reason for the inabilty of current HIV treatment strategies to cure the infection. The possibility of reactivating latent HIV, and thus purging a person of latent HIV reservoirs, has prompted the search for HIV activating agents, but to date these efforts have not yielded tenable therapies. A clinical trial using a recombinant anti-CD3 antibody, and IL-2 to reactivate latent HIV was discontinued due to potent general T-cell activation and cytokine storm. Viral reactivation in the absence of global T cell activation is needed to avoid overproduction of inflammatory cytokines; not to mention the expansion of the latent HIV reservoir due to T cell proliferation. Plants are a rich source of molecules capable of modulating many human immunological responses, including activation of signaling pathways responsible for reactivation of latent HIV-1. We have identified 120 extracts from medicinal plants that are capable of reactivating latent HIV-1. Of these extracts, a significant proportion were found to spare T-cell activation and, therefore, constitute excellent candidates for viral eradication strategies. Based on these results, we conclude that the goal of identifying selective small molecule HIV activators with the desired qualities is possible. More importantly, exploration of these new latency reversing molecules will reveal mechanisms by which they can synergize with agents being explored in the clinic, and act to reactivate HIV in absence of general T cell activation. The mechanisms of action for these botanicals will be compared with the MOAs of known latency reversing agents for which signaling pathways resulting in transcriptional effects are characterized (such as protein kinase C and T-cell receptor agonists and others).