Epigenetic drugs designed to fight cancer might actually be used against many viruses as well. A recent study published in the American Society for Microbiology shows that some pharmaceuticals that act epigenetically have the power to be used as broad spectrum antivirals. Specifically, the researchers looked at histone methyltransferases EZH2/1 inhibitors which can help fight against cancer.
Numerous DNA viruses, such as herpes simplex virus (HSV), are involved in epigenetic regulation which determines productive infection, persistence, and latency. Modulation to the chromatin structure associated with viral genomes is crucial to the virus’ efficacy. Previous research has also shown that the virus can reactivate with the help of histone modifications.
The epigenetic regulation of viruses, including HSV, has been a particular focus of research laboratories, including that of Thomas Kristie, PhD. Dr. Kristie works in the Laboratory of Viral Diseases as a principal investigator at the National Institute of Allergy and Infectious Diseases. His team continues to investigate the virus.
The herpes simplex virus is very common, infecting around 90 percent of people in the U.S., and it can lead to eye infections, cold sores, lesions, and even inflammation of the brain known as encephalitis.
“We have long been interested in the regulation of herpes simplex virus immediate early (IE) genes which are the first set of viral genes to be expressed upon infection,” said Dr. Kristie. “The proteins encoded by these genes are very important regulators, and once expressed, they promote lytic infection as well as reactivation from latency.”
Histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1), according to the research team, are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3-enriched chromatin domain. Several EZH2/1 inhibitors are presently in the development and evaluation process in clinical trials for cancer.
“Some specific cancers are based on “gain of function” mutations in EZH2. Additionally, it has been proposed that in some cancers, these enzymes repress anti-oncogenes and treatment with EZH2/1 inhibitors might result in re-expression of these anti-oncogenes,” said Dr. Kristie.
In their current study, they assessed the influence of a series of EZH2/1 inhibitors on herpes. Because these histone methyltransferase inhibitors have been linked to repressing the gene expression of the herpes virus, the team anticipated to see induction of the virus’s gene expression. However, they uncovered that in vivo and in vitro, the inhibitors reduced HSV gene expression and lytic infection.
“These inhibitors suppressed viral IE gene expression and lytic replication in culture. They also suppressed infection in vivo in a mouse model system and promoted the recruitment of host immune cells to the sites of infection,” said Dr. Kristie.
After analyzing the transcriptome, the researchers found that the epigenetic drugs caused numerous antiviral and stress pathways that were able to account for the compounds’ antiviral activity. The data were consistent with other research studies that showed treatment of cancer cell lines with these epigenetic inhibitors boosted the expression of various genes responsive to cytokines, such as interferons.
Dr. Kristie explained: “Previous studies indicated that this complex would repress HSV infection. However, what was unexpected was treatment with EZH2/1 inhibitors enhanced cellular anti-viral activity and this was dominant over the loss of direct repression of the viral genome by this enzyme complex.”
Mouse sensory ganglia that were latently infected with HSV had enhanced immune responses when they were treated with the epigenetic drugs. Also, this correlated with a decrease in viral reactivation from latency.
Further experiments demonstrated that the anti-viral effects of the EZH2/1 inhibitors reached other DNA viruses, such as adenovirus-5, human Cytomegalovirus, and unrelated Zika RNA virus.
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Dr. Kristie believes that EZH2/1 inhibitors might be utilized to increase a person’s immunity to emerging viruses or viruses that are resistant to drugs. According to Kristie, there aren’t any immediate treatments for emerging viruses, so this could be something doctors can use to boost someone’s innate immunity. It could also be a new method for treating infections by enhancing the infected cell’s own ability to fight the virus.
“Many viruses, such as herpesviruses, have mechanisms to circumvent cellular immune responses. What was striking was that these viruses were not able to escape the suppression mediated by these inhibitors.”
Source: Arbuckle, J.H. and Kristie, T.M. et al. (2017). Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens. mBio, 8(4).
Reference: ASM Communications. Epigenetic Drugs Show Promise as Antivirals. American Society for Microbiology. 15 Aug 2017. Web.