Medical progress in the world of HIV is nagged by the virus’ ability to become dormant, hide and rebound. A cure, however, is no longer considered a distant pipe dream.
A recent study, “Screening of an FDA-Approved Compound Library Identifies Levosimendan as A Novel anti-HIV-1 Agent that Inhibits Viral Transcription,” published in Volume 146 of Antiviral Research identifies a drug typically used on people suffering from heart failure as harnessing previously unknown anti-HIV effects.
This work was performed by Tsuyoshi Hayashi, Maxime Jean, Huachao Huang, Sydney Simpson, Netty G Santoso, and Jian Zhu from the University of Rochester Medical Center. A few of the researchers involved in the study explained their methods of observation to Science Trends.
978 FDA-approved compounds were screened for their ability to block HIV-1 reactivation and one drug — levosimendan — stood out among the rest.
Fairly recent efforts to permanently suppress HIV includes the popular “block and lock” strategy in an attempt to reach stubborn HIV cells hidden in reservoirs in the body. Latency-promoting agents (LPA) are key to the block and lock strategy. LPAs have been added to cART regimens, although in a limited number, and the long term effects need further study.
The purpose of the study was tco find other potential LPAs among the vast plethora of already-known drugs. Levosimendan is a “calcium-sensitizing positive inotropic drug” and was one of the drugs selected for further study on potential effects that may be useful for the treatment of HIV-1.
“To identify novel HIV-1 LPA candidates,” Tsuyoshi Hayashi and Jian Zhu wrote, “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.”
Levosimendan is typically used for a completely different reason than for controlling HIV — it’s used to treat acute heart failure.
At times, drugs have multiple applications: one drug, many uses. That’s why nearly 1,000 already-approved drugs were combed through for potential bonus applications that could be applied in the world of HIV.
“A new and promising anti-HIV-1 inhibitor, levosimendan,” researchers wrote in the abstract, “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.”
HIV-1 targets and activates CD4+ T cells, causing a virus-induced cytopathic effect and cell apoptosis (programmed cell death). Some, however, survive and revert back to a resting state, forming the HIV-1 latent reservoirs. These cells harbor “transcriptionally silent” HIV-1 proviruses, which retain the ability to produce infectious HIV-1 virions.
The researchers added that levosimendan could be used specifically for its unique abilities to block HIV-1 reactivation. “. . . 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.”
The findings present a whole new library of potential applications for a drug that was originally intended for a completely different application.