Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Pierre et Marie Curie, INSERM U943, Paris, France.
Curr Opin Virol. 2012 Oct;2(5):580-7. doi: 10.1016/j.coviro.2012.08.005. Epub 2012 Sep 12.
Integration of the HIV-1 DNA is required and essential to maintain the viral DNA in the infected cell. Integration process occurs in several events, mainly endonucleolytic processing of the 3' ends of the viral DNA and strand transfer or joining of the viral and cellular DNA. The design and discovery of integrase inhibitors were first focused at targeting the catalytic site of IN with a specific effect on strand transfer. Several integrase inhibitors were developed clinically, two first generation inhibitors, raltegravir and elvitegravir and then two second-generation inhibitors, dolutegravir and MK-2058. Recently, allosteric integrase inhibitors intended to interfere with the integrase-LEDGF/p75 interaction have been designed. These new inhibitors called LEDGINs have an effect on 3' processing and strand transfer. Thus, integrase inhibitors present a real added value in combined treatment for naive and experienced HIV infected patients. Combination experiments of LEDGINs and raltegravir suggest that these inhibitors could act additively despite sharing the same viral target. Future therapy could involve combinations of inhibitors of IN function acting though different binding pockets within IN. The place of this class on HIV inhibitors and their future role in perspective of novel therapies to eliminate latent HIV reservoirs and infection for cure should also be explored.
HIV-1 DNA 的整合对于维持感染细胞中的病毒 DNA 是必需的。整合过程涉及多个事件，主要包括病毒 DNA 3'末端的内切酶处理以及病毒和细胞 DNA 的链转移或连接。整合酶抑制剂的设计和发现最初集中在针对 IN 的催化位点，对链转移具有特定的作用。已经开发了几种整合酶抑制剂，两种第一代抑制剂raltegravir 和elvitegravir，然后是两种第二代抑制剂dolutegravir 和 MK-2058。最近，旨在干扰整合酶-LEDGF/p75 相互作用的别构整合酶抑制剂已经被设计出来。这些称为 LEDGINs 的新型抑制剂对 3' 加工和链转移有影响。因此，整合酶抑制剂在初治和经验丰富的 HIV 感染患者的联合治疗中具有实际的附加价值。LEDGINs 和raltegravir 的联合实验表明，尽管这些抑制剂针对相同的病毒靶点，但它们可以发挥相加作用。未来的治疗可能涉及作用于 IN 内不同结合口袋的 IN 功能抑制剂的组合。还应探讨该类药物在 HIV 抑制剂中的地位及其在消除潜伏 HIV 储库和治疗感染以实现治愈的新型疗法中的未来作用。
