期刊
JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
卷 80, 期 5, 页码 605-613出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAI.0000000000001958
关键词
disulfiram; romidepsin; latency-reversing agents; heterogeneity of HIV reservoir
资金
- European Union's Horizon 2020 research and innovation programme [691119-EU4HIVCURE-H2020-MSCA-RISE-2015]
- European Union's Horizon 2020 research and innovation programme under National Science Centre (Poland)
- European Union's Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant [665778, UMO-2015/19/P/NZ6/02188]
- Belgian Fund for Scientific Research (FRS-FNRS, Belgium)
- Fondation Roi Baudouin
- NEAT program (Networking to Enhance the Use of Economics in Animal Health Education, Research, and Policy Making)
- Walloon Region (Fonds de Maturation)
- Les Amis des Instituts Pasteur a Bruxelles, asbl
- University of Brussels (Action de Recherche Concertee (ARC) grant)
Objectives: 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. Setting and Methods: 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 therapytreated individuals. Results: 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. Conclusions: 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据