Heterogeneous HIV-1 reactivation patterns of disulfiram and combined disulfiram+romidepsin treatments

2019
journal article
article
21
dc.abstract.enObjectives: 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 (PBMCs) isolated from 18 HIV-1+ cART-treated 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.pl
dc.affiliationPion Prorektora ds. badań naukowych i funduszy strukturalnych : Małopolskie Centrum Biotechnologiipl
dc.contributor.authorKula-Păcurar, Anna - 381629 pl
dc.contributor.authorDelacourt, Nadegepl
dc.contributor.authorBouchat, Sophiepl
dc.contributor.authorDarcis, Gillespl
dc.contributor.authorAvettand-Fenoel, Veroniquepl
dc.contributor.authorVerdikt, Roxanepl
dc.contributor.authorCorazza, Francispl
dc.contributor.authorNecsoi, Cocapl
dc.contributor.authorVanhulle, Carollinepl
dc.contributor.authorBendoumou, Maryampl
dc.contributor.authorBurny, Arsenepl
dc.contributor.authorDe Wit, Stephanepl
dc.contributor.authorRouzioux, Christinepl
dc.contributor.authorRohr, Oliverpl
dc.contributor.authorVan Lint, Carinepl
dc.date.accessioned2019-11-26T08:45:13Z
dc.date.available2019-11-26T08:45:13Z
dc.date.issued2019pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.number5pl
dc.description.physical605-613pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume80pl
dc.identifier.doi10.1097/QAI.0000000000001958pl
dc.identifier.eissn1077-9450pl
dc.identifier.issn1525-4135pl
dc.identifier.projectROD UJ / OPpl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/87873
dc.languageengpl
dc.language.containerengpl
dc.rightsUdzielam licencji. Uznanie autorstwa - Użycie niekomercyjne - Bez utworów zależnych 4.0 Międzynarodowa*
dc.rights.licenceInna otwarta licencja
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/legalcode.pl*
dc.share.typeinne
dc.subject.endisulfirampl
dc.subject.enromidepsinpl
dc.subject.enlatency-reversing agentspl
dc.subject.enheterogeneity of HIV reservoirpl
dc.subtypeArticlepl
dc.titleHeterogeneous HIV-1 reactivation patterns of disulfiram and combined disulfiram+romidepsin treatmentspl
dc.title.journalJournal of acquired immune deficiency syndromespl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
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 (PBMCs) isolated from 18 HIV-1+ cART-treated 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.
dc.affiliationpl
Pion Prorektora ds. badań naukowych i funduszy strukturalnych : Małopolskie Centrum Biotechnologii
dc.contributor.authorpl
Kula-Păcurar, Anna - 381629
dc.contributor.authorpl
Delacourt, Nadege
dc.contributor.authorpl
Bouchat, Sophie
dc.contributor.authorpl
Darcis, Gilles
dc.contributor.authorpl
Avettand-Fenoel, Veronique
dc.contributor.authorpl
Verdikt, Roxane
dc.contributor.authorpl
Corazza, Francis
dc.contributor.authorpl
Necsoi, Coca
dc.contributor.authorpl
Vanhulle, Carolline
dc.contributor.authorpl
Bendoumou, Maryam
dc.contributor.authorpl
Burny, Arsene
dc.contributor.authorpl
De Wit, Stephane
dc.contributor.authorpl
Rouzioux, Christine
dc.contributor.authorpl
Rohr, Oliver
dc.contributor.authorpl
Van Lint, Carine
dc.date.accessioned
2019-11-26T08:45:13Z
dc.date.available
2019-11-26T08:45:13Z
dc.date.issuedpl
2019
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.numberpl
5
dc.description.physicalpl
605-613
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
80
dc.identifier.doipl
10.1097/QAI.0000000000001958
dc.identifier.eissnpl
1077-9450
dc.identifier.issnpl
1525-4135
dc.identifier.projectpl
ROD UJ / OP
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/87873
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights*
Udzielam licencji. Uznanie autorstwa - Użycie niekomercyjne - Bez utworów zależnych 4.0 Międzynarodowa
dc.rights.licence
Inna otwarta licencja
dc.rights.uri*
http://creativecommons.org/licenses/by-nc-nd/4.0/legalcode.pl
dc.share.type
inne
dc.subject.enpl
disulfiram
dc.subject.enpl
romidepsin
dc.subject.enpl
latency-reversing agents
dc.subject.enpl
heterogeneity of HIV reservoir
dc.subtypepl
Article
dc.titlepl
Heterogeneous HIV-1 reactivation patterns of disulfiram and combined disulfiram+romidepsin treatments
dc.title.journalpl
Journal of acquired immune deficiency syndromes
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

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