P-TEFb复合体调控潜伏期HIV-1再激活的机制研究

Latent reservoirs of HIV are the primary hurdle to eradication of infection. So far,there is no effective way to eventually eradicate HIV. Methods are currently being developed to reactivate latent HIV, which can be cleared by HAART and the immune system. However，the efficacy and specificity of the available latency activators are in need of major improvement, which can be achieved through the identification and characterization of their relevant molecular targets. P-TEFb was identified as a specific HIV transcription factor，increasing the activity of P-TEFb, the transcription of HIV will be increased too. Recently, we found that P-TEFb exists in a novel complex termed SEC. ELL2 is one of the factors in SEC ,from our preliminary data, it shows that HMBA and SAHA etc., the most widely studied chemical activators of latency, behave like Tat to promote ELL2 expression and interaction with P-TEFb. In order to know function of P-TEFb and formation of SEC in reactivate HIV from latency. This proposed research first test the central hypothesis that by control of P-TEFb and its associated factors and the formation of SEC to reactivate HIV latency. This proposed research may provide a potential target and feasibility of ideas for novel drug screening and provide a brand-new perspective to eventually eradicate latent reservoirs in infected patients.

HIV潜伏感染的病毒库是目前彻底治愈艾滋病的主要障碍，目前临床上并无有效治疗方法。研究上，主要通过药物使潜伏期病毒库活化, 最终通过HAART及自身免疫系统来彻底清除。但现有潜伏激活剂的有效性及特异性需进一步提高，而寻找及鉴定与此相关的靶点是提高药物有效性及特异性的有效手段之一。研究表明，P-TEFb 是HIV转录所必需的因子，其活性与HIV的转录成正比，我们最新研究发现，P-TEFb存在于一个新的名为SEC的复合物中，该复合物中ELL2的表达以及ELL2与P-TEFb的相互作用与现有潜伏激活剂HMBA, SAHA等有密切关系。为了研究该复合体在潜伏期HIV再激活过程中的功能，本项目首次深入的研究通过调节P-TEFb相关结合因子的表达及其在SEC中的组装来再激活潜伏期HIV的可行性，本研究为新的药物筛选模型提供了潜在的靶点和可行性的思路，为最终根治艾滋病提供了一个全新的视角。

HIV 潜伏感染的病毒库是目前彻底治愈艾滋病的主要障碍，由于目前临床上并无有效的治疗方法，研究上主要是通过药物使潜伏期病毒库活化，最终通过HAART及自身免疫系统来彻底清除。而现有的潜伏激活剂存在有效性及特异性等一系列的问题。因此，在本项目中，我们首先研究探讨了与HIV潜伏有关的靶点---P-TEFb及其相关因子（重点是AFF1）对HIV潜伏激活的调控及其机制，为潜伏HIV激活剂的筛选提供了有效的靶点； 同时，利用HIV潜伏激活模型，从我国传统特色中草药库中筛选出可以激活HIV潜伏的药物---虎杖，在对虎杖中有效活性成分鉴定的基础上, 做了进一步的机制研究，确定虎杖可以通过使无活性的7SK snRNP 转化为有活性的P-TEFb，从而激活HIV的转录；且可以和prostratin等现有潜伏激活剂协同作用，为 “shock and kill”疗法的开展奠定了基础，对最终根治艾滋病有重大意义。