Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells

Abstract

Alpha interferon (IFN-␣) is an approved medication for chronic hepatitis B. Gamma interferon (IFN-␥) is a key mediator of host innate and adaptive antiviral immunity against hepatitis B virus (HBV) infection in vivo.In an effort to elucidate the antiviral mechanism of these cytokines, 37 IFN-stimulated genes (ISGs), which are highly inducible in hepatocytes, were tested for their ability to inhibit HBV replication upon overexpression in human hepatoma cells. One ISG candidate, indoleamine 2,3-dioxygenase (IDO), an IFN-␥-induced enzyme catalyzing tryptophan degradation, efficiently reduced the level of intracellular HBV DNA without altering the steady-state level of viral RNA. Furthermore, expression of an enzymatically inactive IDO mutant did not inhibit HBV replication, and tryptophan supplementation in culture completely restored HBV replication in IDO-expressing cells, indicating that the antiviral effect elicited by IDO is mediated by tryptophan deprivation. Interestingly, IDO-mediated tryptophan deprivation preferentially inhibited viral protein translation and genome replication but did not significantly alter global cellular protein synthesis. Finally, tryptophan supplementation was able to completely restore HBV replication in IFN-␥-but not IFN-␣-treated cells, which strongly argues that IDO is the primary mediator of IFN-␥-elicited antiviral response against HBV in human hepatocyte-derived cells.Hepatitis B virus (HBV) is a hepatotropic virus in the family of Hepadnaviridae (18, 56) which has infected two billion people worldwide. Although most infected adults can resolve the infection, approximately 5 to 10% of adulthood infections and more than 90% of neonatal infections become lifelong persistent, which causes a significant public health burden currently affecting more than 350 million individuals worldwide (36,41). Patients with chronic hepatitis B carry a high risk of cirrhosis and primary hepatocellular carcinoma (5, 36).It is generally believed that the outcomes of HBV infection and disease pathogenesis are primarily determined by the host adaptive antiviral immune response (9). The resolution of HBV infection is associated with a robust, polyclonal viral antigen-specific cytotoxic T lymphocyte (CTL) response that kills and/or noncytopathically cures virally infected hepatocytes. The latter effect is primarily mediated by inflammatory cytokines, including gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) (17,18,20,21). Interestingly, although it has been shown that HBV can evade host innate immunity surveillance, as evidenced by its failure to induce the expression of interferon-stimulated genes (ISGs) in the liver of chimpanzees during the early phase of infection (66), the virus is sensitive to IFN-␣/␤-induced antiviral response in transgenic mice and in people (30,49). For example, treatment of chronic hepatitis B with pegylated IFN-␣ for 48 weeks can achieve sustained virological response in 30 to 40% of the treated patients (29).In efforts to elucidate the antiviral mechanism ...

Immunotherapy with Costimulatory Dendritic Cells To Control Autoimmune Inflammation

“…The expression of IDO by costimulatory DCs is further reinforced under conditions of immune activation, after reverse signaling by T cells through GITR ligand or CD80/CD86 or stimulation by IFN-g or TLR ligands. Recruitment of IDO + macrophages, B cells, and stromal cells also occurs through this mechanism (16,17).…”

Inhibition of Alpha Interferon (IFN-α)-Induced MicroRNA-122 Negatively Affects the Anti-Hepatitis B Virus Efficiency of IFN-α

“…We found that miR-122 acts as an HBV suppressor miRNA, indicating that IFN-␣-induced miR-122 inhibition may attenuate the anti-HBV activity of IFN-␣. IFN-␣ is capable of inducing hundreds of genes (ISGs), and their antiviral effects have been studied extensively (8,9,(48)(49)(50). However, the exact role of each ISG still remains unclear, and even controversial (15,51).…”

“…Both in vitro and in vivo studies have shown that besides a stimulating effect on cytotoxic T lymphocytes and natural killer cell function, IFN-based therapy (IFN-␣-2b and pegylated IFN-␣-2a or -2b) also has a direct antiviral effect by preventing the formation or accelerating decay of viral capsids and/or inducing antiviral ISGs that inhibit HBV expression and replication (8)(9)(10)(11)(12)(13). Inhibition of IFN-␣ signaling by HBV has been suggested to antagonize the IFN response (14).…”

Maintenance of rat hepatocytes under inflammation by coculture with human orbital fat-derived stem cells

“…Indeed, the secretome of ADSCs has been shown to possess the capability of immunomodulation [19]. It is well known that IL-6, IDO, IFNγ and TNF-α are modulators of the hepatocyte immune response and regeneration [20][21][22][23]. We examined production of the four cytokines in the supernatant and found a high level of IL-6 in the coculture medium, while in the rat hepatocyte monoculture, IL-6 concentration was too low to be measured by ELISA.…”