Additive Effects of Zinc Chloride on the Suppression of Hepatitis A Virus Replication by Interferon in Human Hepatoma Huh7 Cells

Abstract

Background/Aim: Hepatitis A virus (HAV) infection is still one of the serious health problems worldwide, despite the existence of effective vaccines for HAV. Zinc compounds have antiviral activities against various DNA and RNA viruses. Therefore, we investigated the effects of zinc compounds on the antiviral activity of interferon against HAV. Materials and Methods: The effects of zinc compounds with or without interferon on HAV genotype IIIA HA11-1299 replication were examined in human hepatoma Huh7 cells. Cell viability was examined by the MTS assay. Inflammasome associated gene expression was examined by real-time reverse transcription-polymerase chain reaction. Results: Both zinc sulfate and zinc chloride had an inhibitory effect on HAV replication. Zinc sulfate tended to enhance while zinc chloride significantly enhanced the anti-HAV effect induced by interferon-alpha-2a. Zinc chloride significantly up-regulated mitogen-activated protein kinase 12 (MAPK12) and downregulated 6 related genes [baculoviral IAP repeat containing 3 (BIRC3), interleukin 1 beta (IL1B), proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), prostaglandinendoperoxide synthase 2 (PTGS2), PYD and CARD domain containing (PYCARD), and tumor necrosis factor (TNF)]. Conclusion: Zinc chloride inhibits HAV replication and has additive effects on the anti-HAV activities of interferon.

Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication

“…In the present study, we revealed the following: (i) zinc chloride affects the TLR signaling pathways in human hepatocytes; (ii) MAP2K3 expression is downregulated by zinc chloride; and (iii) HAV replication is downregulated by the silencing MAP2K3 expression. Our results explained one of the different mechanisms of the inhibitory effects of zinc compounds on HAV replication from previous reports [ 9 , 10 ].…”

“…We previously reported that a treatment of 5 μM zinc chloride for 72 h suppressed HAV genotype IIIA HA11-1299 replication by 62.2% compared with the untreated control in human hepatoma Huh7 cells [ 10 ]. We also observed the additive effects of zinc chloride on the suppression of HAV replication by interferon-α-2a in Huh7 cells [ 10 ]. It is well known that TLR signaling pathways are involved in the eradication of RNA viruses [ 20 ].…”

“…We and others have demonstrated that zinc compounds (zinc sulfate, zinc chloride, zinc oxide and zinc oxide nanoparticles) have anti-HAV properties [ 9 , 10 , 11 ]. For one thing, zinc sulfate inhibits HAV replication while enhancing the expression of glucose-regulated protein 78 (GRP78/Bip), an antiviral that impedes HAV [ 12 , 13 ] in a dose-dependent manner [ 9 , 10 ]. In addition, zinc chloride inhibits HAV replication with or without interferon [ 10 ].…”

“…For one thing, zinc sulfate inhibits HAV replication while enhancing the expression of glucose-regulated protein 78 (GRP78/Bip), an antiviral that impedes HAV [ 12 , 13 ] in a dose-dependent manner [ 9 , 10 ]. In addition, zinc chloride inhibits HAV replication with or without interferon [ 10 ].…”

Male-Dominant Hepatitis A Outbreak Observed among Non-HIV-Infected Persons in the Northern Part of Tokyo, Japan

“…HAV vaccination could prevent MSM from experiencing acute HAV infection, and HAV vaccination should be useful in preventing other people from being infected with HAV. It is possible that the administration of antivirals against HAV would be useful for the prevention of severe HAV infection [26][27][28][29].…”