Impaired interferon induction of human MxA protein in chronic hepatitis B virus infection

Abstract

MxA protein is interferon inducible, and its role as an antiviral mediator is being studied in various viral diseases. Several cytokines, including type 1 interferons (alpha and beta), interleukins 2 and 12, and granulocyte, macrophage, and granulocyte-macrophage colony-stimulating factors, were tested for their ability to induce human MxA protein synthesis in peripheral blood mononuclear cells from 15 chronic hepatitis B virus-infected patients and 6 healthy subjects as controls. Constitutive MxA expression was scarce in patients and controls but increased significantly in response to type I interferons. MxA responsiveness to interferon alpha was diminished significantly in chronic hepatitis B patients, compared with healthy donors (P < 0.05); this effect was more marked in patients with high viremia levels. Interleukins 2 and 12, and none of the colony-stimulating factors tested, induced low, but detectable, MxA protein levels. These results indicate that chronic infection by hepatitis B virus may impair activation of the immune cells and their capacity to respond to type 1 interferons.

Hepatitis B virus downregulates the human interferon-inducible MxA promoter through direct interaction of precore/core proteins

“…In co-transfection experiments with the human MxA promoter and constructs expressing constitutively core (HBc) or precore (HBe) antigens, we have shown a clear inhibition of the reporter activity after IFN induction. This result was consistent in all cell lines tested, showing that the inhibition was not dependent on host cell factors and, thus, that it is not restricted to liver cells, which is in agreement with our previous observations in human mononuclear cells (Fernandez et al, 1997) and with the inhibition reported by others (Rosmorduc et al, 1999) in similar experiments made with defective HBV genomes. The major characteristic of this defective genome is the accumulation of the core protein in the cytoplasm of transfected cells and the authors concluded that this core protein might be involved in the reduced capacity to respond to IFN.…”

“…We found no changes in the baseline levels of the signal transducers Jak1, Stat1 and Stat2 proteins or in the levels of Stat1 and Stat2 phosphorylation. These are the principal mediators associated with the cascade events produced upon binding of IFN-a/b to its receptor in the cytoplasm membrane (Pellegrini & Dusanter-Fourt, 1997), and the observation of unchanged levels of these proteins is in agreement with recent studies (Keskinen et al, 1999;Melen et al, 2000) and with our previous data in blood mononuclear cells isolated from HBV chronically infected patients (Fernandez et al, 1997). Cells from these patients showed a diminished capacity to express the MxA protein but not 29,59-oligoadenylate synthetase, another IFN-inducible gene, which suggests a specific effect over the MxA protein rather than a general interaction at a common signalling pathway.…”

“…A mutation in the precore sequence has been reported that prevents formation of HBe (Carman et al, 1989). Collectively, these findings might explain differences in MxA inducibility among serum HBeAg-negative patients with the precore mutant (Fernandez et al, 1997).…”

“…We have reported previously that PBMCs from HBV chronically infected patients showed a diminished capacity to respond to IFN-a in comparison to mononuclear cells from healthy subjects (Fernandez et al, 1997). Moreover, this impairment was more evident in those patients with a high level of viraemia, which implies a high level of viral protein production, thus indicating a possible interaction of some of the viral proteins with the transcription machinery of the IFN system.…”

“…In this regard, it is not known what mechanisms are involved in HBV resistance to IFN treatment in the remaining patients. We have shown previously (Fernandez et al, 1997) that the ability of peripheral blood mononuclear cells (PBMCs) from HBV chronically infected patients to express the MxA protein upon IFN stimulation in vitro is impaired. Recently, Rosmorduc et al (1999) have shown that HBV defective particles are implicated in a deficient response to IFN-a in Huh7 cells and that this behaviour appears to be mediated by the accumulation of the HBV capsid protein.…”