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

 描述（由申请人提供）：虽然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水平降低至临床检测的检测限以下，但它并不能治愈，并且在大多数患者中检测到持续性病毒血症。静息CD4 T细胞中罕见但极其稳定的HIV原病毒DNA库（即潜伏库）被认为是持续性病毒血症的主要来源。当宿主细胞被召回抗原（或各种细胞因子）重新激活时，这种潜伏病毒库可以产生感染性病毒，如果 cART 停止，则可以重新传播 HIV 感染。根除潜伏病毒库可能会治愈艾滋病毒感染。目前，“踢杀”策略正在正在进行的临床试验中进行测试，作为消除潜在艾滋病毒储存库的药理学方法。该策略涉及使用潜伏期逆转剂 (LRA)，诱导 HIV 脱离潜伏期（“踢”），进而通过病毒细胞病变效应促进受感染细胞死亡（“杀死”）。已经确定了几种不同的 LRA 治疗类别，可以有效地“踢出”HIV 的潜伏期。相比之下，我们对 HIV 感染的静息 CD4 T 细胞的“杀伤”了解极其有限。这项研究的主要目标是全面评估“踢杀”策略中的“杀死”，使用高度纯化的幼稚（TN）和中央记忆（TCM）CD4 T细胞中的新型潜伏期原代细胞模型。总的来说，我们预计这些研究将对艾滋病毒持久性产生重要的见解，并可能有潜力确定新的目标或方法来根除潜在的艾滋病毒感染。此外，它们可以帮助解释正在进行的专注于耗尽潜在艾滋病毒储存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.