Induction of Antiviral Cytidine Deaminases Does Not Explain the Inhibition of Hepatitis B Virus Replication by Interferons

Abstract

Interferons (IFNs) play a major role in the control of hepatitis B virus (HBV), whether as endogenous cytokines limiting the spread of the virus during the acute phase of the infection or as drugs for the treatment of its chronic phase. However, the mechanism by which IFNs inhibit HBV replication has so far remained elusive. Here, we show that type I and II IFN treatment of human hepatocytes induces the production of APOBEC3G (A3G) and, to a lesser extent, that of APOBEC3F (A3F) and APOBEC3B (A3B) but not that of two other cytidine deaminases also endowed with anti-HBV activity, activation-induced cytidine deaminase (AID), and APOBEC1. Most importantly, we reveal that blocking A3B, A3F, and A3G by combining RNA interference and the virion infectivity factor (Vif) protein of human immunodeficiency virus does not abrogate the inhibitory effect of IFNs on HBV. We conclude that these cytidine deaminases are not essential effectors of IFN in its action against this pathogen.More than 350 millions individuals worldwide suffer from chronic hepatitis B virus (HBV) infection (66), a condition that evolves towards liver insufficiency and hepatocellular carcinoma in approximately 15 to 40% of cases (31). However, the majority of de novo HBV infections, except for those occurring during the perinatal period, are cleared during the acute phase. This appears to result largely from noncytopathic host defense mechanisms involving cytokines, most notably interferons (IFNs) (2, 21). A key role for IFN in the biology of HBV infection is further illustrated by studies in animal models of the disease. For instance, HBV-specific T cells from acutely infected chimpanzees produce high levels of gamma IFN (IFN-␥) coincident with viral clearance (23,37). Also, the induction of alpha/beta IFN (IFN-␣/␤) or the production of IFN-␥ by transferred HBV-specific cytotoxic T lymphocytes inhibits HBV replication in the liver of HBV transgenic mice (9,19,20,35). Finally, IFN-␣ is the standard treatment for chronic hepatitis B (17). Although type I and II IFNs are the most important immune regulators of HBV replication, the downstream effectors mediating the inhibitory action of IFN on HBV replication have not yet been identified.

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

“…However, because APOBEC3G is not efficiently induced in HepG2 cells by either IFN-␣ or IFN-␥ (Fig. 2B), in conjunction with the previous reports showing that APOBEC3G is not an essential effector in the IFN-elicited anti-HBV response (35,51), its role in mediating the antiviral effects of IFNs against HBV remains unclear.…”

Inhibition of Hepatitis B Virus Replication by MyD88 Involves Accelerated Degradation of Pregenomic RNA and Nuclear Retention of Pre-S/S RNAs

“…Members of the APOBEC3 family of cytidine deaminases, which have been shown to target a wide range of retroviruses, were reported to inhibit HBV replication (1,26,27,38,45). Whether these enzymes are the main mediators of the action of IFNs on HBV remains controversial (21,32). Recently, TRIM22 was reported to be expressed in response to IFNs and displayed anti-HBV activity both in vitro and in vivo, but it is uncertain whether TRIM22 would displays such an activity at physiological levels (7).…”

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

“…Although it has been reported that these proteins also have activity against HBV, they are not primarily responsible for the anti-HBV activity of IFNs. Thus, HIV vif, even when used in combination with RNA interference to specific APOBEC3 proteins, does not abrogate the inhibitory effect of IFN on HBV (Jost et al, 2007).…”