Bortezomib Inhibits Hepatitis B Virus Replication in Transgenic Mice

Abstract

Pharmacological modulation of cellular proteins as a means to block virus replication has been proposed as an alternative antiviral strategy that may be less susceptible than others to the development of viral drug resistance. Recent evidence indicates that the ubiquitin-proteasome pathway interacts with different aspects of the hepatitis B virus (HBV) life cycle in cell culture models of virus replication. We therefore examined the effect of proteasome inhibition on HBV replication in vivo using HBV transgenic mice. The proteasome inhibitor bortezomib (Velcade) inhibits proteasome activity in vivo and is used therapeutically for the clinical treatment of multiple myeloma. We found that a single intravenous dose of 1 mg of bortezomib/kg of body weight reduced virus replication for as long as 6 days. The inhibition of HBV by bortezomib was dose dependent and occurred at a step in replication subsequent to viral RNA and protein expression. The reduction in HBV replication did not result from nonspecific hepatocellular toxicity and was not mediated indirectly through the induction of an intrahepatic interferon response. Thus, pharmacological manipulation of the ubiquitinproteasome pathway may represent an alternative therapeutic approach for the treatment of chronic HBV infection.

Hepatitis B Virus Induces Expression of Antioxidant Response Element-regulated Genes by Activation of Nrf2

“…Therefore, proteasome activation seems to be a valuable strategy of the infected cells to reduce the stress resulting from misfolded proteins. In accordance to this, an inhibitory effect of proteasome inhibition by bortezomib on HBV replication can be observed in cell culture (see supplemental material) and in HBV transgenic mice (55).…”

“…This might not be sufficient for a strong inhibition of the proteasomal activity based on a direct interaction of HBx with the proteasome (50). Moreover, recent data demonstrated that inhibition of the proteasomal activity impair HBV replication, arguing against an inhibitory effect of HBx on the proteasome (55). In addition, it was reported recently that HBx induces the degradation of insulin receptor substrate 1 via the ubiquitin-proteasome pathway (60).…”

Hepatitis C virus core protein inhibits E6AP expression via DNA methylation to escape from ubiquitin-dependent proteasomal degradation

“…E6AP is also associated with degradation of another tumor suppressor pRb by HCV NS5B protein [42]. The positive role of the UPS in virus replication was further demonstrated by proteasome inhibitors that interfere with the replication of several human pathogens such as herpesviruses [43,44], hepadnaviruses [45], and influenza viruses [46].…”

Hepatitis B Reactivation in a Multiple Myeloma Patient with Resolved Hepatitis B Infection during Bortezomib Therapy : Case Report

“…11 One report stated that BOR suppresses HBV proliferation in vitro. 12 Two reports described HBV reactivation in patients receiving BOR therapy for myeloma. One study described a patient treated with BOR as salvage therapy after ASCT, 7 and another study described an HBsAg-positive patient discontinuing lamivudine prophylaxis.…”