School of Pharmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Laboratory for Rare & Uncommon Disease of Shandong Province, No 6699, Qingdao Road, Ji'nan 250117, China; Key Laboratory of Forensic Toxicology, Ministry of Public Security, Beijing 100192, China.
Shandong University, No 72, Binhai Road, Qingdao 266237, China.
Molecules. 2022 Dec 20;28(1):3. doi: 10.3390/molecules28010003.
The existence of latent viral reservoirs (LVRs), also called latent cells, has long been an acknowledged stubborn hurdle for effective treatment of HIV-1/AIDS. This stable and heterogeneous reservoir, which mainly exists in resting memory CD4 T cells, is not only resistant to highly active antiretroviral therapy (HAART) but cannot be detected by the immune system, leading to rapid drug resistance and viral rebound once antiviral treatment is interrupted. Accordingly, various functional cure strategies have been proposed to combat this barrier, among which one of the widely accepted and utilized protocols is the so-called 'shock-and-kill' regimen. The protocol begins with latency-reversing agents (LRAs), either alone or in combination, to reactivate the latent HIV-1 proviruses, then eliminates them by viral cytopathic mechanisms (e.g., currently available antiviral drugs) or by the immune killing function of the immune system (e.g., NK and CD8+ T cells). In this review, we focuse on the currently explored small molecular LRAs, with emphasis on their mechanism-directed drug targets, binding modes and structure-relationship activity (SAR) profiles, aiming to provide safer and more effective remedies for treating HIV-1 infection.
潜伏病毒库（LVRs）的存在，也称为潜伏细胞，长期以来一直是有效治疗 HIV-1/AIDS 的公认难题。这种稳定且异质的储库主要存在于静止记忆 CD4 T 细胞中，不仅对高效抗逆转录病毒治疗（HAART）有抗性，而且免疫系统无法检测到，导致一旦中断抗病毒治疗，就会迅速产生耐药性和病毒反弹。因此，已经提出了各种功能性治愈策略来对抗这一障碍，其中一种被广泛接受和利用的方案是所谓的“休克和杀伤”方案。该方案首先使用潜伏逆转剂（LRAs），单独或联合使用，以重新激活潜伏的 HIV-1 前病毒，然后通过病毒细胞病变机制（例如，目前可用的抗病毒药物）或通过免疫系统的免疫杀伤功能（例如，NK 和 CD8+T 细胞）将其消除。在这篇综述中，我们重点关注目前探索的小分子 LRAs，强调其基于机制的药物靶点、结合模式和结构-活性关系（SAR）特征，旨在为治疗 HIV-1 感染提供更安全、更有效的治疗方法。
