Experimental Cancer Drug May Fight Herpes Virus

Epigenetic drugs have the potential to be repurposed as broad-spectrum antivirals, according to findings from a new study published by mBio. The authors found that histone methyltransferase EZH2/1 inhibitors may be able to fight several viruses, including herpes simplex virus (HSV).

Many viruses are subject to epigenetic regulation, meaning that infection, persistence, and latency are determined by the modulation of chromatic linked to viral genomes, according to the authors.

The researchers previously focused on the epigenetic regulation of HSV, which affects a large number of individuals around the world. The infection can recur and ranges from mild lesions to severe ocular or nerve damage.

"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 principal investigator Thomas Kristie, PhD. "The proteins encoded by these genes are very important regulators, and once expressed, they promote lytic infection as well as reactivation from latency."

EXH2/1 are histone-lysine N-methyltrasnferase enzymes that are epigenetic repressors that inhibit gene transcription through propagation of repressive H3K27me3 enriched chromatin domains, the authors wrote.

Currently EZH2/1 inhibitors are being explored as a cancer treatment.

"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," Dr Kristie said.

In the new study, the authors examined how EZH2/1 inhibitors would affect HSV. Since EZH1 and EZH2 have been observed to repress HSV, the authors expected to see viral gene expression.

However, the investigators discovered that the inhibitors reduced HSV gene expression and lytic infection in vitro and in vivo, according to the study.

"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," Dr Kristie said.

Transcriptome analyses showed that the drugs resulted in antiviral and stress pathways that could explain the antiviral potential of the compounds, according to the study. The authors reported that these findings were consistent with other studies that showed the drugs resulted in increased expression of interferon-responsive genes in cancer cell lines.

"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," Dr Kristie said.

The authors also found mouse sensory ganglia that had a latent HSV infection treated with the drugs resulted in increased immune responses linked to a reduction HSV reactivation.

Further experiments showed antiviral effects of the inhibitors spanned to other viruses, including human Cytomegalovirus and adenovirus-5, and the Zika RNA virus, according to the study.

The authors hypothesize that the inhibitors could increase immunity to new viruses or drug-resistant ones.

"For emerging viruses for which there aren't any immediate treatments, this may be something that could be used to boost an individual's innate immunity. This could also be a novel way of treating infections by enhancing the infected cell's own ability to fight the virus," Dr Kristie concluded. "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."