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

Abstract

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.

Novel Role of UHRF1 in DNA methylation-mediated repression of latent HIV-1

“…This heterogeneity and the multiplicity of the silencing mechanisms underlying HIV-1 latency rather than latency in itself are now considered as the major barrier to eradicating HIV-1 (8). In agreement, LRAs have been found to present various reactivation potencies in vitro and ex vivo (45)(46)(47). In the context of DNA methylation, our previous study has highlighted that the DNA methylation inhibitor 5-AzadC exhibits different ex vivo reactivation potencies in terms of HIV-1 latency reversal (18).…”

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…Targeting and reactivating latent cells is challenging due to the heterogeneous nature of the viral reservoirs. Recent studies demonstrating diverse responses of infected cells to LRAs point to their weak effect (Archin et al, 2012;Spivak et al, 2014;Elliott et al, 2015) and highlight the diversity of determinants responsible for the reservoirs' heterogeneity that were demonstrated so far to be virus genetic background- (Norton et al, 2019), cell model- (Spina et al, 2013), cell type- (Baxter et al, 2016;Grau-Expósito et al, 2019;Kula et al, 2019), silencing mechanism- (Elliott et al, 2014;Yukl et al, 2018), tissue reservoir- (Elliott et al, 2014;Telwatte et al, 2018;Yukl et al, 2018), integration site- (Chen et al, 2017;Abner et al, 2018;Battivelli et al, 2018), patient- (Darcis et al, 2017;Yukl et al, 2018), and gender- (Das et al, 2018) specific. In addition, some studies demonstrate a heterogeneous effect of LRAs on NK cells (Garrido et al, 2016) and cytotoxic T-cell lymphocyte (Walker-Sperling et al, 2016) activity with conflicting observations, suggesting either an immunosuppressive effect or a reduced impact of LRA activity on cells sensing HIV-1 reactivation (Archin et al, 2012;Jones et al, 2014;Clutton et al, 2016;Walker-Sperling et al, 2016;Desimio et al, 2017Desimio et al, , 2018.…”

“…Additionally, the effects may also be cell type-specific. We have also recently demonstrated that disulfiram exhibited limited reactivation spectra, being active only in myeloid-derived HIV-1 latently infected cell lines (U1, THP89GFP monocytic, and CHME-5/HIV-1 microglial cells) but not in Jurkat-based T-cell lines (Kula et al, 2019). These heterogeneous cellular responses to LRAs indicate that distinct and cell-type dependent molecular mechanisms contribute to HIV-1 latency in diverse reservoirs.…”

Synergistic Chromatin-Modifying Treatments Reactivate Latent HIV and Decrease Migration of Multiple Host-Cell Types

“…LRA cocktails can either target a specific cell type or globally affect all cell types in the latent reservoir. However, it has been shown that LRA cocktails do not globally affect all latently infected cells equally [52]. To evaluate the potential that the LRAs have on latent reactivation in monocytes, we established an in vitro monocytic model of latency (TLat).…”