Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

Abstract

Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged “block and lock” approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clinical use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compound library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFα-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4+ T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug.

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

“…In this context, the Tat inhibitor didehydro-cortistatin A (dCA) has shown its ability to inhibit ex vivo residual viral replication under ART and to prolong the time to viral reactivation after treatment interruption (Kessing et al, 2017), but some in vitro resistance mutations to dCA were reported (Mousseau et al, 2019). Currently, several drugs are identified for their ability to be used as LPA (Latency Promoting Agents) to ensure a functional cure (Suzuki et al, 2013;Wan and Chen, 2014;Vranckx et al, 2016;Hayashi et al, 2017;Jean et al, 2017;Debyser et al, 2018). Undeniably several strategies must be exploited in order to reach a functional cure.…”

Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation

“…The Planelles model of HIV-1 latency was used to generate latently infected CD4 + T cells with slight modifications (Bosque and Planelles, 2009 ; Hayashi et al, 2017 ; Huang et al, 2017 ). Briefly, naïve CD4 + T cells were isolated from two healthy PBMC donors and were stimulated with anti-CD3/CD28 antibodies that were precoated on a Nunc-Immuno Maxi Sorp plate (Thermo Scientific).…”

Discovery of novel elongator protein 2 inhibitors by compound library screening using surface plasmon resonance

“…These two compound libraries can provide suitable objects to be investigated for new inhibitors. [26][27][28][29][30][31][32][33] Thus, we focused on these two commercial compound libraries and performed high-throughput screening to seek new Elp2 inhibitors.…”