Levosimendan: A FDA-Approved Drug Treating Heart Failure Also Blocks HIV-1 Reactivation

Human immunodeficiency virus type 1 (HIV-1) infection causes acquired immune deficiency syndrome (AIDS), which remains a major public health concern. Combination antiretroviral therapy (cART), typically consisting three or more antiretroviral drugs, has been shown to efficiently block active HIV-1 replication, which leads to an improved life expectancy of HIV-infected patients. Nevertheless, HIV-1/AIDS is still an incurable disease, because cART is unable to completely eliminate HIV-1 due to the presence of HIV-1 latent reservoir being resistant to antiretroviral drugs.

Activated CD4+ T cells are primary targets for HIV-1 infection and resting memory CD4+ T cells are considered to be a major HIV-1 latent reservoir. In most activated CD4+ T cells, HIV-1 infection causes a virus-induced cytopathic effect and cell apoptosis. However, some survive and revert back to their resting state, forming the HIV-1 latent reservoirs. These cells harbor replication competent, but transcriptionally silent HIV-1 proviruses, which retain the capability to produce infectious HIV-1 virions. Since cART is only able to inhibit active HIV-1 replication, it cannot eliminate HIV-1 latently infected cells. Viruses would rebound if the treatment is discontinued, and therefore patients are required to adhere to HIV-1 medicine for life.

tsuyMuch effort has been currently taken in developing strategies to eliminate or permanently suppress HIV-1 latent reservoirs. One promising approach is “block and lock strategy”, aiming to “block” occasional reactivation of HIV-1 proviruses so that integrated proviruses are “locked” in a deep and permanent latency. Since none of the antiretroviral drugs in cART regimen inhibits HIV-1 transcription, there is still sporadically reactivation HIV-1 expression (“blip”) that continues the replenishment of HIV-1 latent reservoir and maintains its persistence.

For the “block and lock” strategy, latency-promoting agents (LPAs) will be complemented with cART regimen to suppress resurrected viral transcription. Such combination treatment will facilitate the decay of HIV-1 latent reservoir and significantly reduce its size, which would eventually lead to the elimination of HIV-1 latent reservoir and a functional cure of HIV-1. However, only a few LPAs have been identified so far, and their safety and long-term effect in vivo still needs further investigation. Therefore, expansion of new potential LPAs will benefit further exploration of  “block and lock” strategy.

To identify novel HIV-1 LPA candidates, we screened an FDA-approved compound library, composed of 978 unique small-molecule compounds using HIV-1 latently infected cell line. A novel and promising anti-HIV-1 transcription inhibitor, levosimendan, was identified from these screens. Levosimendan is a calcium-sensitizing positive inotropic drug and currently used to treat acutely decompensated heart failure in clinics.

Our results demonstrated that this compound strongly inhibits TNFα-induced HIV-1 transcription and reactivation in multiple HIV-1 latency cell lines through affecting the HIV-1 Tat-LTR transcriptional axis. Importantly, we showed that levosimendan blocks HIV-1 reactivation in CD4+ T cells isolated from cART-treated, HIV-infected aviremic patients without cytotoxicity. Levosimendan could be immediately moved to in vivo studies to evaluate whether this compound can be used as LPA since it is an FDA-approved compound.

These findings are described in the article entitled Screening of an FDA-Approved Compound Library Identifies Levosimendan as A Novel anti-HIV-1 Agent that Inhibits Viral Transcription, recently published in the journal Antiviral Research. This work was conducted by Tsuyoshi Hayashi, Maxime Jean, Huachao Huang, Sydney Simpson, Netty G Santoso, and Jian Zhu from the University of Rochester Medical Center.

Speak Your Mind!

READ THIS NEXT

How Does The Brain Relate To Working Memory In Young Children?

Have you ever repeated a phone number over and over in your mind in order to remember it, yet forgot […]

A Hangover Pill May Soon Hit The Market As Clinical Trials Show Potential

A pill to cure the hangover may soon be available after clinical trails see success treating the condition. It is […]

Increases In Minimum Wages Lead To Decreases In Smoking

Published by Paul Leigh University of California Davis School of Medicine and Center for Poverty Research These findings are described […]

Tropical Temperatures At The Cretaceous Poles

Evidence that the polar regions were much warmer during the Cretaceous Period (145-66 million years ago) compared to today has […]

Of Kids And Cats: Placebo By Proxy

Treatment responses in (small) children are difficult to assess since descriptions of symptoms and symptom changes are not easily available […]

Octlantis: The Newly Discovered Octopus City

Recently scientists have discovered a bustling community of approximately 15 gloomy octopi, also known as the Common Sydney Octopus, and […]

Next Generation Industrial Biotechnology: An Alternative To Costly Chemical Procedures

Industrial biotechnology aims to use bioprocessing of sustainable agriculture products, such as starch, fatty acids and/or cellulose, to produce bulk […]