Alpha interferon (IFN-α) is an approved medication for
chronic hepatitis B.
Gamma interferon (IFN-γ) 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-γ-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-γ- but not IFN-α-treated cells, which strongly argues that IDO is the primary mediator of IFN-γ-elicited
antiviral response against HBV in human hepatocyte-derived cells.