New genetic targets IDed for HCV treatment

DNA changes on the IFNL3 gene have been associated with better treatment responses and natural ability to clear infection among patients with hepatitis C infection.

New genetic targets IDed for potential HCV treatment
New genetic targets IDed for potential HCV treatment

Two single-letter DNA changes on the IFNL3 gene on chromosome 19 have been associated with better treatment responses and natural ability to clear infection among patients with hepatitis C infection, and may offer novel targets for therapy, according to researchers.

“[The IFNL3 gene], has received considerable attention in the field of HCV, as many independent genome-wide association studies have identified a strong association between polymorphisms near IFNL3 and clearance of HCV,” Ram Savan, PhD, assistant professor of immunology at the University of Washington in Seattle and colleagues reported in Nature Immunology. “However, the mechanism underlying this association has remained elusive.”

Previous study findings have shown that patients of Asian descent with HCV respond better to treatment when compared with those of African descent. So researchers pooled data from entire human genomes in hopes of identifying gene clusters associated with a response to therapy for HCV.

Two single-letter genetic variations on the IFNL3 gene located near an area that encodes for interleukin-28B, a cytokine known to play a role in the body's immune defense against viruses, may play a role in the body's ability to control HCV infection.

Individuals who carry the T (for thymidine) variant have an unfavorable outcome in fighting HCV, while those who carry the G (for guanosine) variant have a favorable outcome, the researchers found.

Their data showed that HCV could induce liver cells to target the activities of the IFNL3 gene with two microRNAs. MicroRNAs are silencers: They stop the messengers who transmit information to produce a protein from a gene, in this case the production of the antiviral interferon lambda-3.

These two particular microRNAs are generally turned off in liver cells, until HCV coerces them to act on its behalf. Normally, these so called myomiRs are associated with myosin-encoding genes in skeletal and heart muscle.

"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.

Adding support to this suggestion is the researchers' observation that the bad-acting microRNAs in question could not land on and repress interferon lambda-3, if the host carried the favorable "G" variant. In those cases, the host is able to escape adverse regulation by HCV, the researchers observed.

“Our data reveal a previously unknown mechanism by which HCV attenuates the antiviral response and indicate new potential therapeutic targets for HCV treatment,” the researchers concluded.

References

  1. McFarland AP et al. Nature Immun. 2014;15:72-81.

Disclosure: See study for full list of disclosures.

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