Abstract
Hepatitis B virus (HBV) is a human pathogen that has infected an estimated two billion people worldwide. Despite the availability of highly efficacious vaccines, universal screening of the blood supply for virus, and potent direct acting anti-viral drugs, there are more than 250 million carriers of HBV who are at risk for the sequential development of hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). More than 800,000 deaths per year are attributed to chronic hepatitis B. Many different therapeutic approaches have been developed to block virus replication, and although effective, none are curative. These treatments have little or no impact upon the portions of integrated HBV DNA, which often encode the virus regulatory protein, HBx. Although given little attention, HBx is an important therapeutic target because it contributes importantly to (a) HBV replication, (b) in protecting infected cells from immune mediated destruction during chronic infection, and (c) in the development of HCC. Thus, the development of therapies targeting HBx, combined with other established therapies, will provide a functional cure that will target virus replication and further reduce or eliminate both the morbidity and mortality associated with chronic liver disease and HCC. Simultaneous targeting of all these characteristics underscores the importance of developing therapies against HBx.
Highlights
Hepatitis B virus (HBV) is a major etiologic agent responsible for the development of chronic liver disease (CLD) which may resolve or progress to hepatocellular carcinoma (HCC)
There are a variety of treatment options for patients with chronic hepatitis B associated HCC, prognosis and subsequent survival is poor, in part, because diagnosis is often made late, which limits the potential success of available treatments
Many of the properties that promote CLD progression overlap with hallmarks of cancer [4], suggesting that HBx contributes to HCC by epigenetically altering patterns of host gene expression [2], while immune mediated CLD is the host contribution to tumor development [5]
Summary
HBV is a major etiologic agent responsible for the development of chronic liver disease (CLD) which may resolve or progress to HCC. HBx, as the regulatory protein of HBV, binds to the HBV mini-chromosome in vivo, thereby trans-activating virus gene expression and replication [19], suggesting that targeting HBx may contribute to the elimination of cccDNA in combination with one or more other therapeutic approaches.
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