Scientists Look at Role of DNA Variant and Novel Mechanism in Hepatitis C Virus


Researchers wanting to untangle the genetic aspect of the hepatitis C virus that allows it to resist treatment discovered that one particular DNA variant acts like a powerful weapon that helps some people to better fight the disease.

Researchers wanting to untangle the genetic aspect of the hepatitis C virus that allows it to resist some medical therapies discovered that one particular DNA variant acts like a powerful weapon that helps some people to better fight the disease.

In a study conducted at the University of Washington in Seattle, scientists found that the hepatitis C virus (HCV) has a built-in mechanism that can outmaneuver antiviral responses. This previously unrecognized tactic enables the virus to sustain itself longer by weakening the antiviral response, even in the face of drugs introduced in the body to wipe it out.

The details of these findings suggest potential targets for treating HCV, according to Ram Savan, assistant professor of immunology at the University of Washington, who led a team of researchers on the study that was published in the January issue of the journal Nature Immunology.

The hepatitis C virus engages the human immune system in constant battle, each trying to overcome the others latest move. This study adds to a list of previously uncovered HCV mechanisms that the virus uses to outwit the body’s immune system.

A long lasting HCV infection can damage the liver and lead to liver cancer. Typical treatment for HCV involves a triple-drug therapy of interferon injection, ribavirin and direct-acting antiviral agents. Hepatitis C virus genotype 1 carrier’s response rate is generally lower than patients with HCV genotype 2 and 3.

Patients treated for the virus are cured about 70 percent of the time, Savan said. However, resistant strains of HCV sometimes emerge in people who have taken antivirals to rid the infection. Some patients undergo lengthy treatments and endure toxic side effects with little benefit.

This study looked at variants in the interferon-lambda 3 (IFNL3) gene, which were previously identified by researchers investigating why people of Asian descent reacted better to HCV treatment than did those of African descent. The variants are single-letter DNA code changes located near an area that encodes for IFNL3 and are linked to treatment response and a natural ability to clear the viral infection.

The difference between those patients who could effectively clear HCV and those who couldn’t lies in that single letter variation in the IFNL3 gene, Savan said. The outcome was favorable for those who carry the G (for guanosine) variant and unfavorable for those who carry the T (for thymidine) variant.

In this study, researchers discovered a viral evasion mechanism whereby the virus coerces two microRNAs‑‑which otherwise lie dormant in liver cells‑‑to spring into action and reduce the expression of the antiviral IFNL3 gene.

“These two microRNAs are usually not expressed in the liver,” Savan said. “They are mostly expressed in the heart and skeletal muscle.”

If scientists could find a way to stop HCV’s control over these specific microRNAs, such a discovery has the potential to become an important part of treating infection with HCV and slowing the progression to cirrhosis and liver cancer.

"This is a previously unknown strategy by which HCV evades the immune system and suggests that these microRNAs could be therapeutic targets for restoring the host antiviral response,” the researchers wrote in their paper. Adding support to this suggestion is the researchers' observation that the bad-acting microRNAs in question could not target and repress theIFNL3 gene if the host carried the favorable "G" variant.

The findings on this mechanism may also help to explain the strong genetic association with HCV clearance and non-clearance, Savan said. “We want to investigate mechanisms where we (can) better understand how HCV evades the interferon response so that we can develop better treatments against the virus.”

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