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

• Published in: Antiviral research Vol. 146; pp. 76 - 85
• Main Authors: Hayashi, Tsuyoshi, Jean, Maxime, Huang, Huachao, Simpson, Sydney, Santoso, Netty G., Zhu, Jian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2017
• Subjects: Anti-HIV Agents - chemistry; Anti-HIV Agents - isolation & purification; Anti-HIV Agents - pharmacology; CD4+ T cell; Cell Line; Drug Approval; Drug Discovery - methods; FDA-approved compound; Gene Expression Regulation, Viral - drug effects; HIV cure; HIV Infections - drug therapy; HIV Infections - virology; HIV Long Terminal Repeat - drug effects; HIV-1 - drug effects; HIV-1 - physiology; Humans; Hydrazones - isolation & purification; Hydrazones - pharmacology; Levosimendan; Pyridazines - isolation & purification; Pyridazines - pharmacology; Simendan; Small Molecule Libraries; Transcription, Genetic - drug effects; Transcriptional suppression; Virus Activation - drug effects; Virus Latency - drug effects; CD4+ T cell; FDA-approved compound; Levosimendan; HIV cure; Transcriptional suppression; CD4(+) T cell
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2017.08.013

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. •978 FDA-approved compounds were screened for their ability to block TNFα-induced HIV-1 reactivation.•Levosimendan was identified as a novel and leading anti-HIV-1 inhibitor from the screenings.•Levosimendan blocked HIV-1 reactivation in CD4+ T cells isolated from cART-treated, HIV-infected aviremic patients.•Levosimendan suppressed HIV-1 Tat-LTR mediated transcription, which was rescued by inhibition of the PI3K pathway.