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Researchers Block HBV Replication

Enzyme shared by HBV and HIV offers new drug target (Feb. 4)

Researchers at the Saint Louis University School of Medicine in St. Louis, Mo., have reported a potential breakthrough in the pursuit of drugs that could help cure hepatitis B virus (HBV) infection. The investigators were able to measure and then block a previously unstudied enzyme to stop the virus from replicating, taking advantage of known similarities with another major pathogen, human immunodeficiency virus (HIV).

The new research was published online in PLoS Pathogens.

Lead investigator John Tavis, PhD, says the finding may lead to drugs that, in combination with existing medications, could suppress the virus enough to cure patients.

A person who is infected with HBV can have up to a billion viral copies per drop of blood. To cure a patient, a drug needs to reduce those levels to zero.

While existing medications are powerful, they cannot quite deliver a “knockout punch” to HBV. The drugs approved to treat the virus can reduce its numbers, make symptoms disappear for years, and push it to the brink of extinction. But for most people, available medications can’t kill the virus completely. As long as any virus remains, it can multiply and grow strong again.

Both HBV and HIV replicate by reverse transcription. In this process, viral DNA is converted to RNA and then converted back to DNA by two viral enzymes, both of which are vital to the virus’ replication.

The first of these enzymes, a DNA polymerase, has been well studied in the laboratory. The five most commonly used HBV drugs are able to treat — but not cure — the infection by blocking this enzyme.

The second enzyme, ribonuclease H (RNAseH), had eluded investigators in the lab. With no means to measure it, researchers hit dead ends, even though they believed the enzyme was a promising target.

So, with five approved drugs targeting the first enzyme and none aimed at the second, Tavis investigated RNAseH for nearly 20 years.

Because HBV and HIV both use reverse transcription — the mechanism by which they copy themselves in the body’s cells — HBV researchers have been able to benefit from advances in HIV research. Tavis believed that the two viruses might share chemical similarities that could be exploited. Once an assay for the RNAseH enzyme was developed, he and his team were able to test his theory.

The researchers found evidence that a number of the techniques that stop HIV — including inhibitors of HIV RNAseH — could also inhibit HBV RNAseH, showing that the parallels held true. From there, Tavis and his team went on to show that HBV replication could be stopped in cells with compounds that target the elusive second enzyme, RNAseH. With these promising advances, the investigators say that the search for anti-HBV RNAseH drugs is now feasible.

Source: Saint Louis University; February 4, 2013.

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