Pathogens & Inflammation/EPILAB Laboratory, UPRES EA4266, University of Franche-Comté, COMUE Bourgogne Franche-Comté University, 25030 Besançon , France.
Department of Virology, CHRU Besançon, 25030 Besançon, France.
Viruses. 2018 Apr 13;10(4):190. doi: 10.3390/v10040190.
Akt signaling plays a central role in many biological processes that are key players in human immunodeficiency virus 1 (HIV-1) pathogenesis. The persistence of latent reservoirs in successfully treated patients, mainly located in macrophages and latently infected resting CD4+ T cells, remains a major obstacle in HIV-1 eradication. We assessed the in vitro effects of an HIV protease inhibitor (PI) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) on HIV-1 Nef-induced Akt activation in macrophages and on HIV-1 reactivation in U1 monocytoid cells. Ex vivo, we investigated the impact of combination antiretroviral therapy (cART) on Akt activation, as measured by flow cytometry, and on the viral reservoir size, quantified by qPCR, in monocytes and autologous resting CD4+ T cells from HIV-infected individuals (Trial registration: NCT02858414). We found that, in myeloid cells, both Akt activation and HIV-1 reactivation were inhibited by PI but not by NNRTI in vitro. Our results indicate that cART decreases Akt activation and reduces the size of the HIV reservoir in both monocytes and resting CD4+ T cells. Our study indicates that Akt activation could play a role in HIV reservoir formation, indicating that drugs which target Akt could be efficient for limiting its size in aviremic chronically infected patients.
Akt 信号转导在许多生物学过程中发挥着核心作用，这些过程是人类免疫缺陷病毒 1（HIV-1）发病机制的关键因素。成功治疗的患者中潜伏储库的持续存在，主要位于巨噬细胞和潜伏感染的静止 CD4+T 细胞中，仍然是 HIV-1 根除的主要障碍。我们评估了 HIV 蛋白酶抑制剂（PI）和非核苷类逆转录酶抑制剂（NNRTI）对巨噬细胞中 HIV-1 Nef 诱导的 Akt 激活以及 U1 单核细胞样细胞中 HIV-1 再激活的体外作用。在体外，我们通过流式细胞术研究了联合抗逆转录病毒疗法（cART）对 Akt 激活的影响，并通过 qPCR 定量检测了 HIV 感染者单核细胞和自体静止 CD4+T 细胞中病毒库的大小（试验注册：NCT02858414）。我们发现，在髓样细胞中，PI 可抑制 Akt 激活和 HIV-1 再激活，但 NNRTI 则不能。我们的结果表明，cART 可降低 Akt 激活并减少单核细胞和静止 CD4+T 细胞中 HIV 储库的大小。我们的研究表明，Akt 激活可能在 HIV 储库形成中起作用，这表明针对 Akt 的药物可能有效限制无病毒慢性感染患者中其大小。
