Datta Prasun K, Kaminski Rafal, Hu Wenhui, Pirrone Vanessa, Sullivan Neil T, Nonnemacher Michael R, Dampier Will, Wigdahl Brian, Khalili Kamel
Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, 7th Floor, Philadelphia, PA 19140, USA.
Curr HIV Res. 2016;14(5):431-441. doi: 10.2174/1570162x14666160324125536.
It is well established that antiretroviral therapy (ART), while highly effective in controlling HIV replication, cannot eliminate virus from the body. Therefore, the majority of HIV-1-infected individuals remain at risk for developing AIDS due to persistence of infected reservoir cells serving as a source of virus re-emergence. Several reservoirs containing replication competent HIV-1 have been identified, most notably CD4+ T cells. Cells of the myeloid lineage, which are the first line of defense against pathogens and participate in HIV dissemination into sanctuary organs, also serve as cellular reservoirs of HIV-1. In latently infected resting CD4+ T cells, the integrated copies of proviral DNA remain in a dormant state, yet possess the ability to produce replication competent virus after cellular activation. Studies have demonstrated that modification of chromatin structure plays a role in establishing persistence, in part suggesting that latency is, controlled epigenetically.
Current efforts to eradicate HIV-1 from this cell population focus primarily on a "shock and kill" approach through cellular reactivation to trigger elimination of virus producing cells by cytolysis or host immune responses. However, studies revealed several limitations to this approach that require more investigation to assess its clinical application. Recent advances in gene editing technology prompted use of this approach for inactivating integrated proviral DNA in the genome of latently infected cells. This technology, which requires a detailed understanding of the viral genetics and robust delivery, may serve as a powerful strategy to eliminate the latent reservoir in the host leading to a sterile cure of AIDS.
众所周知，抗逆转录病毒疗法（ART）虽然在控制HIV复制方面非常有效，但无法从体内清除病毒。因此，由于作为病毒重新出现来源的受感染储存细胞持续存在，大多数HIV-1感染者仍有患艾滋病的风险。已经确定了几个含有具有复制能力的HIV-1的储存库，最显著的是CD4+T细胞。髓系谱系细胞是抵御病原体的第一道防线，并参与HIV向免疫赦免器官的传播，它们也作为HIV-1的细胞储存库。在潜伏感染的静止CD4+T细胞中，前病毒DNA的整合拷贝处于休眠状态，但在细胞激活后具有产生具有复制能力的病毒的能力。研究表明，染色质结构的改变在建立持续性方面起作用，部分表明潜伏期是由表观遗传控制的。
目前从该细胞群体中根除HIV-1的努力主要集中在通过细胞重新激活来触发细胞溶解或宿主免疫反应以消除病毒产生细胞的“激活并杀死”方法。然而，研究揭示了这种方法的几个局限性，需要更多的研究来评估其临床应用。基因编辑技术的最新进展促使使用这种方法来灭活潜伏感染细胞基因组中的整合前病毒DNA。这种技术需要对病毒遗传学有详细的了解和强大的递送能力，可能是消除宿主中潜伏储存库从而实现艾滋病无菌治愈的有力策略。
