IFN-γ: A Crucial Player in the Fight Against HBV Infection?

Abstract

About 0.8 million people die because of hepatitis B virus (HBV) infection each year. In around 5% of infected adults, the immune system is ineffective in countering HBV infection, leading to chronic hepatitis B (CHB). CHB is associated with hepatocellular carcinoma, which can lead to patient death. Unfortunately, although current treatments against CHB allow control of HBV infection, they are unable to achieve complete eradication of the virus. Cytokines of the IFN family represent part of the innate immune system and are key players in virus elimination. IFN secretion induces the expression of interferon stimulated genes, producing proteins that have antiviral properties and that are essential to cell-autonomous immunity. IFN-α is commonly used as a therapeutic approach for CHB. In addition, IFN-γ has been identified as the main IFN family member responsible for HBV eradication during acute infection. In this review, we summarize the key evidence gained from cellular or animal models of HBV replication or infection concerning the potential anti-HBV roles of IFN-γ with a particular focus on some IFN-γ-inducible genes.

Keywords: Chronic infection; Hepatitis B virus; Innate immunity; Interferon-gamma; Interferon-stimulated genes.

Figure 1. HBV life cycle.

HBV recognizes its receptor, NTCP, at the cell membrane (1). The virus enters the cell via endocytosis (2) and releases its genome (rcDNA) in the cytoplasm (3). rcDNA is repaired to form cccDNA in the nucleus (4) and transcribed to form mRNA (5). mRNAs are translated into viral proteins in the cytoplasm (6). pgRNA is encapsidated to form an immature nucleocapsid (7) and reverse transcribed to form rcDNA (8). Mature capsid and membrane proteins are assembled in multivesicular bodies (9) and secreted (10). Alternatively, newly synthetized rcDNA can re-enter the nucleus to increase the cccDNA pool (9′). MVB, multivesicular body; LE, late endosome.

Figure 2. ISGs involved in the elimination of HBV under the control of IFN-γ.

The APOBEC family can be induced by IFN-γ and has antiviral activities against HBV. APOBEC3A and APOBEC3B, whose expression is induced by IFN-γ, were shown to decrease HBV DNA levels. The APOBEC3G antiviral mechanism remains uncertain. It may inhibit HBV pgRNA packaging or inhibit HBV DNA reverse transcription in a deaminase-independent manner. ISG20 can specifically recognize and degrade HBV RNA to inhibit HBV replication and ISG20 cooperates with APOBEC3A to degrade deaminated cccDNA. IDO can be efficiently induced by IFN-γ. IDO decreases the level of HBV DNA and HBV protein synthesis. GBP can target the cellular protease furin, which is hijacked by HBV to facilitate the biosynthesis and maturation of the viral protein HBeAg. MVB, multivesicular body; LE, late endosome.