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Antiviral Res. 2017 Oct;146:76-85. doi: 10.1016/j.antiviral.2017.08.013. Epub 2017 Aug 24.

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

Author information

1
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
2
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, 14642, USA; Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, 14642, USA. Electronic address: Jian_Zhu@urmc.rochester.edu.

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.

KEYWORDS:

CD4(+) T cell; FDA-approved compound; HIV cure; Levosimendan; Transcriptional suppression

PMID:
28842263
PMCID:
PMC5654649
DOI:
10.1016/j.antiviral.2017.08.013
[Indexed for MEDLINE]
Free PMC Article

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