The "Kick" Revisited in the "Kick and Kill" Strategy

 描述(申请人提供)：尽管联合抗逆转录病毒疗法(CART)可以将大多数感染者的血浆HIV RNA水平降低到临床检测的检测下限以下，但它不是治愈的，在大多数患者中检测到持续性病毒血症。在静止的CD4T细胞中罕见但非常稳定的艾滋病毒前病毒DNA储存库(即潜伏储存库)被认为是持续性病毒血症的主要来源。当宿主细胞被Recall抗原(或各种细胞因子)重新激活时，这种潜伏的蓄水池会产生传染性病毒，如果CART停止生产，可能会重新传播HIV感染。根除潜伏的蓄水池可能会治愈艾滋病毒感染。目前，正在进行的临床试验中正在测试一种“踢杀”策略，作为一种耗尽潜在艾滋病毒宿主的药理学方法。这一策略涉及给药潜伏期反转剂(LRA)，诱导艾滋病毒脱离潜伏期(“Kick”)，进而通过病毒的细胞病变效应(“Kit”)促进受感染细胞的死亡。已经确定了几种不同的LRA治疗类别，它们有效地“踢”出了HIV的潜伏期。相比之下，我们对HIV感染的静止的CD4T细胞的“杀伤”作用的了解是极其有限的。这项研究的主要目标是使用新的原代细胞模型对高纯度的幼稚(TN)和中央记忆(Tcm)CD4T细胞的潜伏期进行全面评估。总的来说，我们预计这些研究将对HIV的持久性产生重要的见解，并可能有可能找到新的靶点或方法来根除潜伏性HIV感染。此外，它们还可以帮助解释正在进行的专注于耗尽HIV潜伏库的试验的临床发现。

 DESCRIPTION (provided by applicant): Although combination antiretroviral therapy (cART) can reduce plasma HIV RNA levels in most infected individuals to below the detection limit of clinical assays, it is not curative and persistent viremia is detected in the majority of patients.A rare, but extremely stable, HIV proviral DNA reservoir in resting CD4+ T cells (i.e. the latent reservoir) is thought to be the major source of persistent viremia. This latent reservoir can produce infectious virus when the host cell is reactivated by recall antigen (or by various cytokines), that can reseed HIV infection if cART is discontinued. Eradication of the latent reservoir may lead to a cure for HIV infection. Currently, a "kick and kill" strategy is being testd in ongoing clinical trials as a pharmacological approach to deplete the latent HIV reservoir. This strategy involves the administration of a latency reversing agent (LRA) which induces HIV out of latency (the "kick"), that in turn facilitates death of the infected cells by viral cytopathic effets (the "kill"). Several distinct therapeutic classes of LRAs have been identified that effectively "kick" HIV out of latency. In contrast, our understanding of the "kill" in HIV-infected resting CD4 T cells is extremely limited. The primary goal of this study is to comprehensively assess the "kill in the "kick and kill" strategy, using novel primary cell models of latency in highly purified naïe (TN) and central memory (TCM) CD4+ T cells. Collectively, we anticipate that these studies will yield important insights into HIV persistence, and may have the potential to identify new targets or approaches to eradicate latent HIV infection. Furthermore, they could help explain clinical finding from ongoing trials that are focused on depleting the latent HIV reservoir.