Service of Molecular Virology, Département de Biologie Moléculaire (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
Malopolska Centre of Biotechnology, Laboratory of Virology, Jagiellonian University, Krakow, Poland.
J Acquir Immune Defic Syndr. 2019 Apr 15;80(5):605-613. doi: 10.1097/QAI.0000000000001958.
Few single latency-reversing agents (LRAs) have been tested in vivo, and only some of them have demonstrated an effect, albeit weak, on the decrease of latent reservoir. Therefore, other LRAs and combinations of LRAs need to be assessed. Here, we evaluated the potential of combined treatments of therapeutically promising LRAs, disulfiram and romidepsin.
We assessed the reactivation potential of individual disulfiram or simultaneous or sequential combined treatments with romidepsin in vitro in latently infected cell lines of T-lymphoid and myeloid origins and in ex vivo cultures of CD8-depleted peripheral blood mononuclear cells isolated from 18 HIV-1 combination antiretroviral therapy-treated individuals.
We demonstrated heterogeneous reactivation effects of disulfiram in vitro in various cell lines of myeloid origin and no latency reversal neither in vitro in T-lymphoid cells nor ex vivo, even if doses corresponding to maximal plasmatic concentration or higher were tested. Disulfiram+romidepsin combined treatments produced distinct reactivation patterns in vitro. Ex vivo, the combined treatments showed a modest reactivation effect when used simultaneously as opposed to no viral reactivation for the corresponding sequential treatment.
Exclusive reactivation effects of disulfiram in myeloid latency cell lines suggest that disulfiram could be a potential LRA for this neglected reservoir. Moreover, distinct reactivation profiles pinpoint heterogeneity of the latent reservoir and confirm that the mechanisms that contribute to HIV latency are diverse. Importantly, disulfiram+romidepsin treatments are not potent ex vivo and most likely do not represent an effective drug combination to achieve high levels of latency reversal in vivo.
在体内测试的单一潜伏逆转剂 (LRA) 很少，其中只有一些对减少潜伏库有微弱的效果。因此，需要评估其他 LRA 和 LRA 组合。在这里，我们评估了联合治疗有前途的 LRA 二硫化四乙基秋兰姆和罗米地辛的潜在作用。
我们评估了单独使用二硫化四乙基秋兰姆或同时或序贯联合使用罗米地辛在体外潜伏感染的 T 淋巴细胞和髓系来源细胞系以及从 18 名接受 HIV-1 联合抗逆转录病毒治疗的个体分离的 CD8 耗尽外周血单个核细胞的体外培养物中的再激活潜力。
我们证明了二硫化四乙基秋兰姆在各种髓系来源的细胞系中的体外再激活作用具有异质性，并且在体外 T 淋巴细胞中或体外均未产生潜伏逆转，即使测试了与最大血浆浓度或更高对应的剂量。二硫化四乙基秋兰姆+罗米地辛联合治疗在体外产生了不同的再激活模式。在体外，联合治疗同时使用时表现出适度的再激活作用，而相应的序贯治疗则没有病毒再激活。
二硫化四乙基秋兰姆在髓样潜伏细胞系中的单独再激活作用表明，二硫化四乙基秋兰姆可能是这种被忽视的储库的潜在 LRA。此外，不同的再激活谱指出潜伏储库的异质性，并证实有助于 HIV 潜伏的机制是多样化的。重要的是，二硫化四乙基秋兰姆+罗米地辛治疗在体外并不有效，并且不太可能代表在体内实现高潜伏逆转水平的有效药物组合。
