Antiviral activity of zinc against hepatitis viruses: current status and future prospects

Abstract

Viral hepatitis is a major public health concern globally. World health organization aims at eliminating viral hepatitis as a public health threat by 2030. Among the hepatitis causing viruses, hepatitis B and C are primarily transmitted via contaminated blood. Hepatitis A and E, which gets transmitted primarily via the feco-oral route, are the leading cause of acute viral hepatitis. Although vaccines are available against some of these viruses, new cases continue to be reported. There is an urgent need to devise a potent yet economical antiviral strategy against the hepatitis-causing viruses (denoted as hepatitis viruses) for achieving global elimination of viral hepatitis. Although zinc was known to mankind for a long time (since before Christ era), it was identified as an element in 1746 and its importance for human health was discovered in 1963 by the pioneering work of Dr. Ananda S. Prasad. A series of follow up studies involving zinc supplementation as a therapy demonstrated zinc as an essential element for humans, leading to establishment of a recommended dietary allowance (RDA) of 15 milligram zinc [United States RDA for zinc]. Being an essential component of many cellular enzymes and transcription factors, zinc is vital for growth and homeostasis of most living organisms, including human. Importantly, several studies indicate potent antiviral activity of zinc. Multiple studies have demonstrated antiviral activity of zinc against viruses that cause hepatitis. This article provides a comprehensive overview of the findings on antiviral activity of zinc against hepatitis viruses, discusses the mechanisms underlying the antiviral properties of zinc and summarizes the prospects of harnessing the therapeutic benefit of zinc supplementation therapy in reducing the disease burden due to viral hepatitis.

Keywords: hepatitis A virus; hepatitis B virus; hepatitis C; hepatitis E virus; viral hepatitis; zinc.

Figure 1

Effect of zinc on hepatitis viruses. A simplified scheme of life cycle of HAV, HCV and HEV is shown. Note that HAV and HEV are quasi-enveloped whereas HCV is an enveloped virus. Zinc salts (ZnCl₂, ZnSO₄), ZnO nanoparticles (NP) and ZnO tetrapod-shaped nanoparticles (TP) inhibits the replication of Hepatitis A (HAV), Hepatitis C (HCV) and Hepatitis E viruses (HEV). Zinc finger antiviral protein (ZAP) binds to CpG motifs in HEV RNA and HBV pre-genomic (pg) RNA and targets them for degradation.

Figure 2

Effect of zinc on Vaccinia and Herpes simplex virus-2. Schematic showing the life cycle of Vaccinia virus (A) Herpes Simplex virus-2 (B). ‘’ indicates the steps inhibited by zinc.

Figure 3

Effect of zinc on RNA viruses. Schematic showing the effect of zinc on life cycle of RNA viruses. Apart from directly inhibiting different stages of viral life cycle, zinc mediates its antiviral activity through zinc-containing proteins such as ZAP and ZMPSTE24. ZAP binds to CpG motif in viral RNA and targets them for exosomal degradation. ZMPSTE24 and IFITM complex interferes with entry of viruses. EV D68, enterovirus D68; HPV, human papilloma virus; RSV, respiratory syncytial virus; TGEV, transmissible gastroenteritis virus; SFV, Semliki forest virus; SARS-CoV, severe acute respiratory syndrome coronavirus; FMDV, foot and mouth disease virus; HIV-1, human immunodeficiency virus-1; IAV, influenza A virus; VSV, vesicular stomatitis virus; PRRSV, porcien reproductive and respiratory syndrome virus; MHV, mouse hepatitis virus. ‘’ indicates the steps inhibited by zinc.

Figure 4

Zinc-Metallothionein homeostasis and zinc signaling in monocytes, macrophages and dendritic cells. LPS mediated stimulation of TLR4 leads to activation of NFκB, IRF3, and MAPK signaling pathways, resulting in production of type I IFNs and ZIP8. Zinc mobilization via ZIP8 increases intracellular zinc level, which acts on MAPK, NFκB, and IRF3 signaling pathways by inhibiting dual specificity phosphatase (DUSP) and by inhibiting IKKβ and IRF3 phosphorylation. Metal Responsive element-binding transcription factor-1 (MTF-1) promotes the synthesis of metallothioneins (MT), which in turn binds to and translocates zinc into organelles. MTF-1 also activates the synthesis of ZnT1, which exports zinc out of the cell. ‘’ indicates the steps inhibited by zinc.

Figure 5

Subcellular localization of Zinc transporters (ZnTs), Zrt- and Irt- like proteins (ZIPs) and Metallothionein (MT). Red arrow indicates the flow of Zn²⁺ from cytosol to cellular organelles via ZnTs and green arrow indicates the flow of Zn²⁺ from cellular organelles to cytosol via ZIPs. Brown arrow indicates the ZIPs located on plasma membrane, which transports zinc inside the cytosol. Orange arrow indicates the ZnTs located on plasma membrane, which transports zinc outside the cell. MTs translocate zinc into nucleus, golgi, endoplasmic reticulum (ER), mitochondria and lysosomes.

Figure 6

Zinc signaling in T cells. TCR stimulation induces ZAP70 mediated phosphorylation of ZIP6, leading to its localization to the immunological synapse in lipid rafts (yellow). ZIP6 mediates Zn²⁺ influx, which inhibits SHP-1 mediated dephosphorylation of the LCK and DUSP mediated dephosphorylation of the MAPKs. ZIP8 is present on the lysosome and it mobilizes lysosomal Zn²⁺ to cytoplasm, which inhibits Calcineurin mediated dephosphorylation of CREB, leading to CREB mediated transcriptional upregulation of IFNγ and perforin. ‘’ indicates the steps inhibited by zinc.