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Heterogeneous HIV-1 Reactivation Patterns of Disulfiram and Combined Disulfiram+Romidepsin Treatments

Kula, Anna, PhDa,b; Delacourt, Nadège, MSca; Bouchat, Sophie, PhDa; Darcis, Gilles, MD, PhDa,c,d; Avettand-Fenoel, Veronique, PhDe,f; Verdikt, Roxane, MSca; Corazza, Francis, MD, PhDg; Necsoi, Coca, MD, PhDh; Vanhulle, Caroline, MSca; Bendoumou, Maryam, MSca; Burny, Arsene, PhDa; De Wit, Stephane, MD, PhDh; Rouzioux, Christine, PhDe,f; Rohr, Oliver, PhDi,j; Van Lint, Carine, PhDa

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 15, 2019 - Volume 80 - Issue 5 - p 605–613
doi: 10.1097/QAI.0000000000001958
Translational Research
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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 therapy–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.

aService of Molecular Virology, Département de Biologie Moléculaire (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium;

bMalopolska Centre of Biotechnology, Laboratory of Virology, Jagiellonian University, Krakow, Poland;

cAcademic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands;

dInfectious Diseases Department, Liege University Hospital, Liege, Belgium;

eService de Virologie, Université Paris-Descartes, AP-HP, Hopital Necker-Enfants Malades, Paris, France;

fUniversité Paris Descartes, Sorbonne Paris Cité, Paris, France;

gLaboratory of Immunology, Brugmann University Hospital, Université Libre de Bruxelles (ULB), Bruxelles, Belgium;

hService des Maladies Infectieuses, CHU St-Pierre, ULB, Bruxelles, Belgium;

iUniversité de Strasbourg, laboratoire DHPI EA7292, Schiltigheim, France; and

jIUT Louis Pasteur, Université de Strasbourg, Schiltigheim, France.

Correspondence to: Carine Van Lint, Service of Molecular Virology, Département de Biologie Moléculaire (DBM), Université Libre de Bruxelles (ULB), Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium (e-mail: cvlint@ulb.ac.be).

Supported by the European Union's Horizon 2020 research and innovation programme under grant agreement No 691119-EU4HIVCURE-H2020-MSCA-RISE-2015 to C.V.L. and under the National Science Centre (Poland) and Marie Skłodowska-Curie grant agreement no. 665778, Polonez Grant UMO-2015/19/P/NZ6/02188 to A.K. Work in C.V.L.'s laboratory was supported from the Belgian Fund for Scientific Research (FRS-FNRS, Belgium), the “Fondation Roi Baudouin”, the NEAT program (Networking to Enhance the Use of Economics in Animal Health Education, Research, and Policy Making), the Walloon Region (Fonds de Maturation), “Les Amis des Instituts Pasteur à Bruxelles, asbl, and the University of Brussels (Action de Recherche Concertée (ARC) grant). The laboratory of C.V.L. is part of the ULB-Cancer Research Centre (U-CRC). A.K. is a postdoctoral fellow of ”Les Amis des Instituts Pasteur à Bruxelles, asbl. C.V.L. is “Directeur de Recherches” of the FRS-FNRS (Belgium), respectively.

The authors declare no competing financial interests.

The authors S.B. and G.D. have equally contributed to the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

Received June 28, 2018

Accepted December 03, 2018

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