Evaluating a New Class of AKT/mTOR Activators for HIV Latency-Reversing Activity Ex Vivo and In Vivo
Evaluating a New Class of AKT/mTOR Activators for HIV Latency-Reversing Activity Ex Vivo and In Vivo
复制标题
DOI：
10.1128/jvi.02393-20
复制
发表时间：
2021-04-01
影响因子：
5.4
通讯作者：
Greene, Warner C.
中科院分区：
文献类型：
--
作者：
Gramatica, Andrea;Schwarzer, Roland;Greene, Warner C.
激活潜伏的人类免疫缺陷病毒1型（HIV-1）表达的能力可能有利于许多HIV治疗策略;然而，大多数潜伏期逆转剂（LRA）已被证明是令人失望的。我们评估了AKT/mTOR激活剂作为潜在的新一类LRA。测试了激活AKT/mTOR信号传导的两种糖原合成酶激酶-3抑制剂（GSK-3 i）SB-216763和tideglusib（后者已经处于II期临床试验中）。这些GSK-3 i重新激活存在于来自抗逆转录病毒治疗（ART）的病毒血症个体的血液样品中的潜伏HIV-1，而不存在T细胞活化、炎性细胞因子释放、细胞毒性或细胞毒性T淋巴细胞或NK细胞的效应子功能受损。然而，当对接受抑制性ART的猴免疫缺陷病毒（SIV）感染恒河猴进行体内给药时，tideglusib表现出较差的药效学特性，并且没有明显的SIV潜伏期逆转证据。无论是替代药物制剂或组合的这种药物与其他类别的LRA将导致一个有效的体内潜伏期逆转策略仍有待确定。重要如果与免疫疗法相结合，潜伏期逆转剂（LRA）有可能减少水库的大小足以工程免疫反应可以控制病毒在没有抗逆转录病毒治疗。我们已经鉴定了一类新的LRA，其不诱导T细胞活化并且能够增强而不是抑制CD 81 T和NK细胞细胞毒性效应子功能。这类新的LRA对应于糖原合成酶激酶-3的抑制剂。在这项工作中，我们还研究了这类药物的一个成员，tideglusib，在SIV感染的恒河猴的影响。然而，当在体内测试时，tideglusib显示出不利的药代动力学特性，这导致缺乏SIV潜伏期逆转。我们的离体和体内结果之间的脱节突出了开发具有药理学性质的新型LRA的重要性，这些药理学性质允许在隐藏潜在储库的相关解剖隔室中进行全身药物递送。
An ability to activate latent human immunodeficiency virus type 1 (HIV-1) expression could benefit many HIV cure strategies; however, most latency -reversing agents (LRAs) have proven disappointing. We evaluated AKT/mTOR activators as a potential new class of LRAs. Two glycogen synthase kinase-3 inhibitors (GSK-3i's), SB-216763 and tideglusib (the latter already in phase II clinical trials), that activate AKT/mTOR signaling were tested. These GSK-3i's reactivated latent HIV-1 present in blood samples from aviremic individuals on antiretroviral therapy (ART) in the absence of T cell activation, release of inflammatory cytokines, cell toxicity, or impaired effector function of cytotoxic T lymphocytes or NK cells. However, when administered in vivo to simian immunodeficiency virus (SIV)-infected rhesus macaques on suppressive ART, tideglusib exhibited poor pharmacodynamic properties and resulted in no clear evidence of significant SIV latency reversal. Whether alternative pharmacological formulations or combinations of this drug with other classes of LRAs will lead to an effective in vivo latency-reversing strategy remains to be determined.IMPORTANCE If combined with immune therapeutics, latency-reversing agents (LRAs) have the potential to reduce the size of the reservoir sufficiently that an engineered immune response can control the virus in the absence of antiretroviral therapy. We have identified a new class of LRAs that do not induce T-cell activation and that are able to potentiate, rather than inhibit, CD81 T and NK cell cytotoxic effector functions. This new class of LRAs corresponds to inhibitors of glycogen synthase kinase-3. In this work, we have also studied the effects of one member of this drug class, tideglusib, in SIV-infected rhesus monkeys. When tested in vivo, however, tideglusib showed unfavorable pharmacokinetic properties, which resulted in lack of SIV latency reversal. The disconnect between our ex vivo and in vivo results highlights the importance of developing novel LRAs with pharmacological properties that allow systemic drug delivery in relevant anatomical compartments harboring latent reservoirs.