A large proportion of the world’s population is infected with herpes
simplex virus (HSV), and because most individuals do not present with symptoms, they often are not aware of their status. Primary infection and reactivation of the virus can have negative health implications, ranging from cold sores to mild genital lesions to severe ocular that can result in loss of vision entirely, and therefore, a treatment for the virus is imperative.
Researchers from the National Institute of Allergy and Infectious Diseases at (NIAID) at the National Institutes of Health may have found a solution in a new target for treatments against the virus. They conducted a study
that offers insight into how a particular cellular enzyme complex regulates HSV. Their findings were surprising—by inhibiting the cellular enzyme complex in question, EZH2/1, they were able to suppress the infection. Furthermore, the researchers showed that the EZH2/1 inhibitors “also enhanced the cellular antiviral response in cultured cells in mice,” according to the official press release.
Study authors write that once an individual is infected with HSV, the virus “establishes lifelong latency in sensory neurons.” However, latent genomes can be reactivated and cause recurrent disease. Many of the pharmaceuticals on the market designed to fight against HSV “target the viral DNA polymerase” to stop “late-stage viral replication.”
However, some strains of the virus have developed resistance to these pharmaceuticals, particularly in infected individuals with weakened immune systems. The authors also note that “these [pharmaceuticals] do not adequately control subclinical infectious viral shedding, which is the most prevalent means of transmission.” Because of these limitations, we need new therapeutic approaches to fight HSV.
In the study, the researchers turn to epigenetic therapeutics. Epigenetic regulation “is based on a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development.” Epigenetic modulators
, “which are responsive to changes in the cellular environment and often linked to the nuclear architecture,” according to Nature Reviews: Genetics
, are used in the treatment of several harmful diseases. Epigenetic machinery also regulates herpesviruses, and therefore, epigenetic therapeutics are a novel approach to not only controlling infection, but also controlling persistence of the virus to prevent recurrence.
Past research has found a link between EZH2/1 and the control of lytic and latency stages of several herpesviruses, HSV among them. The authors note that “specific epigenetic inhibitors can modulate HSV lytic infection, latency, and reactivation.”
“Inhibitors of the histone H3K9 demethylases (LSD1, JMJD2) block initiation of HSV infection, while inhibitors of the histone H3K9 and H3K7 demethylases (UTX/JMJD3) block reactivation from latency,” the authors write. “Most strikingly, inhibition of LSD1 in vivo
enhances epigenetic repression of the latent HSV genomes, which correlates with a reduction of reactivation and viral shedding.”
By treating the primary cells with EZH2/1 inhibitors, the researchers managed to suppress HSV gene expression and decrease infection spread to adjacent cells. Furthermore, the EZH2/1 inhibitors also blocked spread of reactivation in a mouse model.
Further investigation into the “antiviral activities” of the EZH2/1 inhibitors showed that “treatment [with the inhibitors] induces multiple components of antipathogen pathways that result in an enhanced cellular antiviral state.”
The authors stress that the antiviral effects of these inhibitors are not just limited to HSV; the inhibitors were also capable of suppressing human cytomegalovirus, adenovirus, and even Zika virus infections, albeit in cell culture “using human primary fibroblast cell lines.” The authors speculate that the EZH2/1 inhibitors “have considerable potential as broad-spectrum antivirals.”
Feature Picture: The spread of herpes simplex virus infection (green) is suppressed in cells treated with EZH2/1 inhibitors (GSK126 or GSK343). Feature Picture Source: National Institutes of Health.
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