Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus

Abstract

Hepatitis B virus (HBV) infection can result in a spectrum of outcomes from immune-mediated control to disease progression, cirrhosis, and liver cancer. The host molecular pathways that influence and contribute to these outcomes need to be defined. Using an immunocompetent mouse model of chronic HBV infection, we identified some of the host cellular and molecular factors that impact on infection outcomes. Here, we show that cellular inhibitor of apoptosis proteins (cIAPs) attenuate TNF signaling during hepatitis B infection, and they restrict the death of infected hepatocytes, thus allowing viral persistence. Animals with a liver-specific cIAP1 and total cIAP2 deficiency efficiently control HBV infection compared with WT mice. This phenotype was partly recapitulated in mice that were deficient in cIAP2 alone. These results indicate that antagonizing the function of cIAPs may promote the clearance of HBV infection.hepatitis B virus | cellular inhibitor of apoptosis proteins | cIAP1 | cIAP2 | TNF I t is estimated that 2 billion people currently living in the world have been infected with hepatitis B virus (HBV), and among these, 360 million people are chronic carriers (1). HBV causes 780,000 deaths each year and is responsible for 50% and 33% of deaths attributable to liver cancer and cirrhosis, respectively (2). The host factors and molecular pathways that impact on HBV disease and clinical outcomes are not well-understood (3). What is becoming clear is that immunosuppressive agents and particularly, biological agents, including anti-TNF therapy, can cause major flares in HBV-related disease, leading to morbidity and mortality (4, 5). Animal models and particularly, immunocompetent mouse models of persistent HBV infection have been used to dissect host-pathogen interactions that influence infection outcomes (6-8). These animal models can be used to define host cell signaling and cell death pathways that contribute to the persistence or control of HBV infection.We induced HBV infection in two mouse models to examine the relevance of host factors in controlling infection. In a model that mimics partial control of infection, we were able to determine the importance of host cell signaling pathways through the use of gene-targeted mice. By identifying the relevant host cell signaling molecules that impact on HBV clinical outcomes, it may be possible to develop therapeutics that target host cell pathways and alter the course of HBV-related disease. ResultsChronic HBV Infection Can Be Mimicked in a Mouse Model. We used a previously described method to induce HBV persistence in immunocompetent mice (6). A plasmid containing a 1.2 over length sequence of HBV genotype A was hydrodynamically injected into mice, but in contrast to the previously published protocol, we did not anesthetize animals. Using this modified technique, we did not observe any injection-associated mortality, and C57BL/6 mice showed persistently high serum HBV DNA levels over 8-12 wk (Fig. 1A). Eventually, HBV DNA levels fell in all animals along with t...

Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis

“…To examine the in vivo efficacy of Smac mimetics in the treatment of HBV infection, we used an immunocompetent mouse model of chronic HBV infection (1,17,18). The model mimics aspects of variability seen in human serum HBV DNA levels during infection, because not all mice, even within strains, behave identically (1).…”

“…hepatitis B virus | cellular inhibitor of apoptosis proteins | TNF | birinapant | Smac mimetic S tudies using animal models indicate that TNF is an important effector cytokine that promotes clearance of hepatitis B virus (HBV) infection (1,2). Compelling human data show that HBVinfected patients, particularly those with detectable serum HBV surface antigen (HBsAg), are at increased risk of HBV reactivation when treated with TNF antagonists (3,4).…”

Hitting the right button: MAVS-mediated defense against HAV infection

“…In HBV infection, no viral immune escape in hepatocytes has been reported, and HBV is rather considered a stealth non-cytopathic virus that evades rather than actively modulates innate immune response [1]. However, a recent study demonstrated that HBV infection upregulates cellular inhibitor of apoptosis proteins (cIAPs) and thereby skews TNF receptor signaling towards survival rather than death in HBVinfected hepatocytes [10]. While viral constituents or viral replication can be revealed by cytosolic immune sensors, it is much more demanding to detect viral persistence forms in hepatocytes, such as HBV cccDNA.…”

New horizon for radical cure of chronic hepatitis B virus infection

“…A novel approach to eliminate HBVcore containing hepa tocytes [85] was based on findings showing that elimination of HBV is impaired by cellular inhibitor of apoptosis proteins (cIAPs), which inhibit the TNFαmediated death of HBVinfected cells [86] . This led to testing the effects of inhibitors of cIAPs, including birinapant and other Smac mimetics, on HBVinfected hepatocytes.…”