Epigenetic Inhibitors Could Help Target Human Cytomegalovirus

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Cytomegalovirus, DNA virus from Herpesviridae family
Cytomegalovirus CMV, a DNA virus from Herpesviridae family. 3D illustration. CMV mostly causes diseases in newborns and immunocompromised patients

Human cytomegalovirus infection can be treated by using epigenetic inhibitors that target bromodomain proteins, suggest study results from the University of Cambridge.

There is a high level—60-95% depending on the country—of dormant human cytomegalovirus (HCMV) infection in the population. Most people will not even realize they are infected and even if their infection becomes active will not experience symptoms.

However, for immunocompromised individuals it can be life threatening. This is particularly true for individuals who undergo organ transplants who need to take immunosuppressants. These drugs appear to trigger reactivation of HCMV and also make it harder for the patient to fight off the infection. As there is no vaccine and current treatments are not highly effective this can be a big problem.

Ian Groves, Ph.D., a researcher at the Cambridge Institute of Therapeutic Immunology and Infectious Disease, and colleagues carried out a study to assess whether epigenetic inhibitors could be the answer to treating HCMV infections in immunocompromised individuals.

Epigenetic inhibitors are a relatively new class of drugs that can influence gene expression by inhibiting DNA methylation or histone deacetylation. To date, several have been approved for the treatment of cancer as they can reactivate tumor suppressor genes and many are still in development for this purpose and also to treat type 2 diabetes related cardiovascular disease.

In this study, which was published in the journal PNAS, Groves and colleagues tested the efficacy of a range of epigenetic inhibitors for treating HCMV infection. HCMV mostly hides in the body in a dormant form. The team wanted to see if they could trigger HCMV infected cell lines to produce viral proteins that could then be better targeted by the immune system.

One type of epigenetic inhibitor that targets bromodomain proteins was successful at reactivating the virus and triggering it to produce proteins in the cell lines. This then allowed immune T-cells in the blood cell cultures to target and kill cells infected with HCMV.

This is the first time that bromodomain proteins have been linked to activation of HCMV. Previously they have been linked to some cancers and multiple sclerosis.

The researchers are now hoping their results can be translated to patients. They are proposing these drugs could be used to treat both recipients and even donors before organ transplants occur.

“We’re looking to purge the patient’s viral reservoir before they go into the operating theatre and before they start taking immunosuppressants, when they would become extremely vulnerable to the virus reactivating. In other words, we’re proposing a pre-emptive strike,” says Groves.

“Prior to transplantation, many patients will have a relatively healthy immune system, so when the virus puts its head above the parapet, its cover is blown, and the immune system will see it and kill the cells it’s been hiding in. Ideally, donors would also be treated to avoid re-infecting recipients.”

This research still needs to be tested in patients, but if their results can be translated into the clinic it could have a big impact on vulnerable, immunocompromised patients.

“This would be the first type of treatment to reduce HCMV infection levels pre-transplant in order to lower the chances of virus reactivation during immune suppression after transplantation. Our findings could lead to thousands of lives being saved every year,” says Groves.

It could also potentially help protect other individuals impacted by HCMV such as pregnant women, as HCMV infection during pregnancy can cause miscarriage and also birth defects such as brain damage and hearing loss.

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