Acchioni Chiara, Palermo Enrico, Sandini Silvia, Acchioni Marta, Hiscott John, Sgarbanti Marco
Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Istituto Pasteur Italia-Cenci Bolognetti Foundation, Viale Regina Elena 291, 00161 Rome, Italy.
Pathogens. 2021 Nov 20;10(11):1517. doi: 10.3390/pathogens10111517.
Despite the success of highly active antiretroviral therapy (HAART), integrated HIV-1 proviral DNA cannot be eradicated from an infected individual. HAART is not able to eliminate latently infected cells that remain invisible to the immune system. Viral sanctuaries in specific tissues and immune-privileged sites may cause residual viral replication that contributes to HIV-1 persistence. The "Shock or Kick, and Kill" approach uses latency reversing agents (LRAs) in the presence of HAART, followed by cell-killing due to viral cytopathic effects and immune-mediated clearance. Different LRAs may be required for the in vivo reactivation of HIV-1 in different CD4 T cell reservoirs, leading to the activation of cellular transcription factors acting on the integrated proviral HIV-1 LTR. An important requirement for LRA drugs is the reactivation of viral transcription and replication without causing a generalized immune activation. Toll-like receptors, RIG-I like receptors, and STING agonists have emerged recently as a new class of LRAs that augment selective apoptosis in reactivated T lymphocytes. The challenge is to extend in vitro observations to HIV-1 positive patients. Further studies are also needed to overcome the mechanisms that protect latently infected cells from reactivation and/or elimination by the immune system. The Block and Lock alternative strategy aims at using latency promoting/inducing agents (LPAs/LIAs) to block the ability of latent proviruses to reactivate transcription in order to achieve a long term lock down of potential residual virus replication. The Shock and Kill and the Block and Lock approaches may not be only alternative to each other, but, if combined together (one after the other), or given all at once [namely "Shoc-K(kill) and B(block)-Lock"], they may represent a better approach to a functional cure.
尽管高效抗逆转录病毒疗法（HAART）取得了成功，但整合的HIV-1前病毒DNA无法从受感染个体中根除。HAART无法消除对免疫系统不可见的潜伏感染细胞。特定组织和免疫特权部位中的病毒庇护所可能导致残余病毒复制，这有助于HIV-1的持续存在。“激活并清除”方法是在HAART存在的情况下使用潜伏逆转剂（LRA），随后由于病毒细胞病变效应和免疫介导的清除作用而导致细胞杀伤。不同的CD4 T细胞库中HIV-1的体内重新激活可能需要不同的LRA，从而导致作用于整合的前病毒HIV-1 LTR的细胞转录因子的激活。LRA药物的一个重要要求是重新激活病毒转录和复制而不引起全身性免疫激活。Toll样受体、RIG-I样受体和STING激动剂最近已成为一类新的LRA，可增强重新激活的T淋巴细胞中的选择性凋亡。挑战在于将体外观察结果扩展到HIV-1阳性患者。还需要进一步研究以克服保护潜伏感染细胞不被免疫系统重新激活和/或清除的机制。“阻断并锁定”替代策略旨在使用潜伏促进/诱导剂（LPA/LIA）来阻断潜伏前病毒重新激活转录的能力，以实现对潜在残余病毒复制的长期锁定。“激活并清除”和“阻断并锁定”方法可能不仅相互替代，而且，如果将它们结合在一起（依次进行），或一次性给予[即“激活（清除）并阻断-锁定”]，它们可能代表一种更好的功能性治愈方法。
