抗CD45RO抗体-JQ1偶联物激活HIV潜伏库的作用及机制研究

当前，抗逆转录病毒联合疗法（cART）已经成功地将艾滋病从一种致死性疾病转变为慢性可控性疾病，但cART并不能彻底治愈病人，一旦停药，患者体内潜伏的HIV会迅速反弹，究其原因是患者体内HIV潜伏储存库的存在。HIV潜伏储存库主要由HIV潜伏感染的静止期记忆性CD4+T细胞构成。如何靶向清除整合在宿主细胞上的前病毒是当前HIV/AIDS治疗领域最富挑战的科学问题。本项目拟采用化学偶联技术，将特异性表达于记忆性CD4+T细胞表面的CD45RO的抗体与HIV潜伏感染逆转剂JQ1偶联，旨在制备一种靶向激活HIV潜伏病毒的抗CD45RO抗体-JQ1偶联物（ACJC）。该偶联物既能保留抗体对记忆性T细胞的靶向性，又能特异性输送小分子药物JQ1到达潜伏T细胞库，从而实现定向激活潜伏HIV。再将其与cART联用，杀灭激活的HIV，为彻底有效靶向清除体内潜伏库，实现HIV“功能性”治愈提供新的思路。

Currently, the cognition of acquired immunodeficiency syndrome (AIDS) has been changed from a fatal disease into a manageable chronic disease successfully by combination antiretroviral therapy (cART). However, complete eradication of HIV with cART seems impossible because of containing a stable reservoir of HIV latent infection in HIV-infected patients. The major HIV reservoir is a small pool of latently infected resting memory CD4+T cells. One of the most challenging issues on HIV-1 latent infection is how to kill the integrated previruses on the host target cells and diminishing the reservoir of HIV. Here, we plan to prepare an anti-CD45RO antibody-JQ1 conjugate (ACJC) by chemical modification. It is expected that the antibody-drug conjugate (ADC) can not only strongly binding to the resting memory CD4+T cells via its anti-CD45RO domains, but also effectively reactivate HIV in latently infected cells by a small molecule chemical JQ1. Most importantly, ACJC will be further administered with effective strategies of cART for killing the virus completely. This study will provide a new idea for complete eradication of HIV latency and achieving a functional HIV cure.