Zinc vs HCV: Researchers confirm inflammatory, antiviral effects against chronic liver disease

Zinc may be a potent weapon in the fight against liver disease, according to research published in Nature Communications.

Specifically, researchers found that zinc may inhibit the inflammatory and antiviral effects of interferon lambda 3 (IFN-λ3)—a protein with strong association with the tissue damage caused by chronic liver disease—and thereby offer protective benefits to patients with hepatitis C virus (HCV) and influenza viruses.

“We have demonstrated that zinc inhibits numerous facets of the liver’s immune response to viruses that may be mediated by IFN-λ3,” said lead author Scott Read, BSc, MSc, PhD, The Westmead Institute for Medical Research, Westmead, NSW, Australia. “Zinc interferes with IFN-λ3 binding to the interferon lambda receptor, which results in decreased antiviral activity and increased viral replication both in vitro and in vivo. Interestingly, zinc also blocks the inflammatory activity of IFN-λ3, which has been strongly linked to accelerated progression to liver cirrhosis in viral and non-viral liver disease. Our data suggest that serum zinc levels in patients with chronic hepatitis C are genetically predetermined by the IFN-λ3 polymorphism, confirming the inhibitory role of zinc in vivo,” he added.

Metallothioneins (MTs) are small proteins with a high affinity for zinc and copper. Both oxidative stress and heavy metals induce MTs, which then facilitate detoxification, free radical scavenging, and metal binding.

In viral infections, MT expression is well documented, but the part they play is—as yet—unknown. Do MTs have an antiviral role or are they simply a consequence of cellular stress?

Dr. Read and fellow researchers conducted this study to characterize the role of MTs after infection with HCV. They assessed the expression and localization of HCV both in vitro and in vivo, using an siRNA knockdown approach to determine their antiviral efficacy.

In vitro, they confirmed MT induction driven by HCV, and with immunofluorescence, showed that MT accumulated in the nucleus of HCV-infected hepatocytes. They found that MTs had slight antiviral effects against the genotype 2a isolate JFH1 strain of HCV in vitro, with an approximately 1.4-fold increase in viral RNA (P < 0.05). The JFH1 strain is the only HCV strain with the ability to replicate efficiently without adaptive mutations and produce HCV particles both in vitro and in vivo.

Finally, Dr. Read and colleagues found that the antiviral effect of zinc against HCV was mediated through the induction of MTs (P < 0.05).

“The data highlight the potential for zinc to be used as a simple and effective treatment against acute and chronic inflammation in the liver,” Dr. Read concluded.

This project was supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant No. 1053206; and a University of Sydney Bridging Support Grant (No. 171673).