HIV病毒潜伏库的形成机制和对策挑战

Formation mechanism and countermeasure challenges of HIV virus latent reservoir

长期以来,病毒潜伏库(latent viral reservoir, LVR)的存在严重阻碍了AIDS的有效治疗,LVR无法被人体免疫系统识别,高效抗逆转录病毒疗法(highly active antiretroviral therapy, HAART)对其无效,一旦中断抗病毒治疗,患者会出现快速耐药和病毒血症反弹。截至目前,研究报道的克服该障碍最常用的方案是"激活并杀死"策略,即应用潜伏库逆转剂(latency-reversing agents, LRAs)重新激活潜伏的HIV-1病毒,再利用抗病毒药物和人体免疫系统杀死激活的病毒;另一种方法是通过不可逆地抑制HIV-1的转录使病毒永久沉默,不再具有转录活化的能力。本文综述了HIV-1 LVR的形成和维持机制以及目前文献中报道的LRAs,并介绍了一种使病毒永久沉默的基因疗法,旨在为HIV-1感染提供更安全有效的治疗方法。

The existence of latent viral reservoir(LVR) has been an acknowledged stubborn hurdle for effective treatment of AIDS for a long time, since this stable reservoir is not resistant to highly active antiretroviral therapy(HAART) and can’t be detected by immune system, leading to drug resistance and rapid viral rebound once antiviral treatment is interrupted. The most accepted protocol to combat this barrier is the use of latency-reversing agents(LRAs) to reactivate the latent HIV-1 virus then eliminate them with antiviral drugs and immune system, which is commonly known as "shock and kill" regimen. The alternative option is to permanently silence HIV-1 provirus by irreversibly inhibiting HIV transcription so that they are no longer viable. In this review, the formation and maintenance mechanism of HIV-1 LVR, as well as the LRAs currently reported have been described herein, a gene therapy that silences virus permanently has also been elaborated, aiming to provide a safer and more effective remedy for HIV infection.