Human immunodeficiency virus-1 (HIV) is one of the most challenging viruses for doctors to treat.
Even with effective antiretroviral therapy, immune cells infected with HIV can hide and lie inactive in certain areas of the body called latent reservoirs. If treatment is discontinued, these reservoirs may become active again, causing patients to face renewed challenges with symptoms of acquired immunodeficiency syndrome (AIDS).
A new study led by Guochun Jiang, PhD, an assistant professor in the Department of Biochemistry and Biophysics at the UNC School of Medicine and a member of the UNC HIV Cure Center, has found that a drug named citarinostat is effective at disrupting latent HIV reservoirs. The findings, which were published in Science Advances, bring researchers one step closer to achieving eradication of the virus.
Guochun Jiang, PhD
"Disruption is the first step required for the so-called 'kick and kill' approach aimed at the eradication of latent HIV reservoirs," said Jiang. "Our study highlights a promising class of drugs that can agitate and force HIV-infected immune cells to come out of latency and be attacked by the immune system."
Antiretroviral therapy (ART), a treatment used for HIV, stops the virus from reproducing and reduces the overall amount of viral load in the body. But, despite its success throughout the rest of the body, ART is not effective against latent reservoirs.
To address this challenge, researchers have explored medications that can re-activate and coerce HIV-infected immune cells to crawl out of latent reservoirs in a controlled manner. This action makes these cells more vulnerable to HIV medications and eradication via the immune system.
Some drugs-particularly histone deacetylase (HDAC) inhibitors-have been explored for this purpose. These drugs work by altering important genetic information termed epigenetics. While these drugs can influence the genetics of the HIV virus, they have shown limited success in fully reversing HIV latency.
In the new study, researchers found that the epigenetic drug citarinostat selectively stops histone decrotonylation (HDCR), a genetic process that allows HIV to successfully fly under the immune system's radar. Citarinostat's big role in histone decrotonylation was previously unknown to researchers.
With this new role in mind, the research team introduced the drug to human white blood cells collected from study participants at UNC-Chapel Hill, as well as microglial cells derived from brain tissue through "The Last Gift" study at the University of California San Diego.
They found that the drug effectively increases histone crotonylation, disrupts latent HIV in immune cells, and induces HIV transcription to successfully agitate and force the HIV-infected immune cells to re-awaken.
"This work not only advances HIV cure research but also identifies histone decrotonylation as a druggable and previously underappreciated target," said Jiang. "The development of selective HDCR inhibitors opens new possibilities for reprogramming gene expression in cancer, neurological disorders, acute kidney injury, and other diseases where dysregulated chromatin states drive pathology," said Jiang.
The UNC HIV Cure Center, BCBP, R. L. Juliano Structural Bioinformatics Core, UNC Eshelman School of Pharmacy, Vaccine & Gene Therapy Institute/Oregon National Primate Research Center, University of California-Davis, and the "Last Gift Program" at University of California - San Diego all contributed to the study.
