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Oct 23, 2012

HBV Target Triggers Viral Replication and Apoptosis

  • Studies in the roundworm Caenorhabditis elegans and human cells have identified the hepatitis B virus (HBV) X protein (HBx) as a promising therapeutic target for chronic hepatitis B virus infection. Studies have previously shown that HBx is critical for HBV infection and pathogenesis, and causally involved in hepatocyte carcinogenesis. However, the cellular targets of the protein and its mechanism of action in HBV pathogenesis haven’t been well characterized.

    A team at the University of Colorado, Boulder, and Xiamen University in China has now shown that HBx interacts with the anti-apoptotic proteins Bcl-2 and Bcl-xL through a Bcl-2 homology 3 (BH3)-like motif in mammalian cells. Their studies in hepatocytes showed that this interaction causes an increase in cytosolic calcium levels and cell death, and increases viral replication. Encouragingly, RNAi knockdown of Bcl-2 or Bcl-xL reduced the elevation in calcium levels induced by HBx and decreased viral replication in hepatocytes.

    Studies in a C. elegans model engineered to express HBx separately demonstrated that expression of HBx induces both necrotic and apoptotic cell death, which are events characteristic of liver infection by HBV. In fact, expression of the protein led to a high percentage of embryonic lethality, and about 97% of embryos didn’t hatch. When the HBx-expressing worms were also engineered to lack either an essential apoptosis gene or a necrosis-related gene, embryonic lethality was partially suppressed. Mirroring data from the hepatocyte studies, genetic and biochemical studies in the roundworm found that HBx interacted directly with the roundworm Bcl-2 homolog CED-9, through a BH3-like motif, and that this triggered the increased cytosolic Ca2+, leading to activation of multiple viral and host events, including HBV replication, assembly, and cell death.

    To find potential targets or effectors of HBx-induced cell killing, the investigators also carried out a genetic screen as a means for identifying mutations that suppressed the embryonic lethality phenotype caused by global expression of HBx in the roundworm. This screen identified dozens of HBx-induced death suppressor mutations, which they say suggests that it may represent a useful tool for identifying new apoptosis and necrosis genes, and potential effectors or targets of HBx.

    “Targeting the BH3-like motif of HBx to prevent HBx binding to Bcl-2 family proteins could be an effective therapeutic strategy for treating HBV-related liver disorders without perturbing host cell-signaling pathways,” the team writes in one of their two published papers in PNAS, titled “Hepatitis B virus X protein targets the Bcl-2 protein CED-9 to induce intracellular Ca2+ increase and cell death in Caenorhabditis elegans”. “Our results suggest that C. elegans could serve as an animal model for identifying crucial host factors and signaling pathways of HBx, and aid in development of strategies to treat HBV-induced liver disorders.”

    In fact, they add, their hepatocyte studies, reported in the second paper published in PNAS, suggest the HBx-Bcl-2 protein interaction could represent a promising intervention point for therapeutic strategies targeting HBV. “Our study suggests that the BH3-like motif of HBx is necessary for HBx binding to Bcl-2 family proteins, which results in elevated cytosolic calcium, efficient viral replication, and HBV-induced cell death. Therefore, therapeutically targeting the BH3-like motif of HBx could be a unique and effective strategy to treat patients with chronic HBV and to prevent development of HCC.” The investigators' second PNAS paper is titled “Hepatitis B virus X protein targets Bcl-2 proteins to increase intracellular calcium, required for virus replication and cell death induction.”


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