Gramatica Andrea, Schwarzer Roland, Brantley William, Varco-Merth Benjamin, Sperber Hannah S, Hull Philip A, Montano Mauricio, Migueles Stephen A, Rosenthal Danielle, Hogan Louise E, Johnson Jeffrey R, Packard Thomas A, Grimmett Zachary W, Herzig Eytan, Besnard Emilie, Nekorchuk Michael, Hsiao Feng, Deeks Steven G, Snape Michael, Kiernan Bernard, Roan Nadia R, Lifson Jeffrey D, Estes Jacob D, Picker Louis J, Verdin Eric, Krogan Nevan J, Henrich Timothy J, Connors Mark, Ott Melanie, Pillai Satish K, Okoye Afam A, Greene Warner C
Gladstone Institute of Virology, Gladstone Institutes, San Francisco, California, USA.
Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
J Virol. 2021 Mar 25;95(8). doi: 10.1128/JVI.02393-20. Epub 2021 Feb 3.
An ability to activate latent HIV-1 expression could benefit many HIV cure strategies, but the first generation of latency reversing agents (LRAs) has 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 to 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 latency-reversing strategy remains to be determined. 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, CD8+ 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 next generation LRAs with pharmacological properties that allow systemic drug delivery in relevant anatomical compartments harboring latent reservoirs.
激活潜伏的HIV-1表达的能力可能会使许多HIV治愈策略受益，但第一代潜伏期逆转剂（LRA）已被证明令人失望。我们评估了AKT/mTOR激活剂作为一类潜在的新型LRA。测试了两种激活AKT/mTOR信号传导的糖原合酶激酶-3抑制剂（GSK-3i），即SB-216763和替地格鲁司（后者已进入II期临床试验）。这些GSK-3i在没有T细胞激活、炎性细胞因子释放、细胞毒性或细胞毒性T淋巴细胞或NK细胞效应功能受损的情况下，重新激活了接受抗逆转录病毒治疗（ART）的病毒血症阴性个体血液样本中潜伏的HIV-1。然而，当将替地格鲁司给予接受抑制性ART的感染SIV的恒河猴时，它表现出不良的药效学特性，并且没有明显的证据表明SIV潜伏期有显著逆转。这种药物的替代药理学配方或与其他类别的LRA联合使用是否会导致有效的潜伏期逆转策略仍有待确定。如果与免疫疗法联合使用，潜伏期逆转剂（LRA）有可能充分减小病毒库的规模，从而使工程化的免疫反应在没有抗逆转录病毒治疗的情况下能够控制病毒。我们已经鉴定出一类新型的LRA，它们不会诱导T细胞激活，并且能够增强而不是抑制CD8 + T和NK细胞的细胞毒性效应功能。这类新型的LRA对应于糖原合酶激酶-3的抑制剂。在这项工作中，我们还研究了这类药物中的一个成员替地格鲁司在感染SIV的恒河猴中的作用。然而，在体内测试时，替地格鲁司显示出不利的药代动力学特性，这导致SIV潜伏期没有逆转。我们的体外和体内结果之间的脱节凸显了开发具有允许在含有潜伏病毒库的相关解剖区域进行全身药物递送的药理学特性的下一代LRA的重要性。
