HBV is an enveloped virus containing a 3.2-kb partially double stranded DNA genome with four open reading frames. These open reading frames encode the reverse transcriptase, precore, and core proteins; three surface antigen proteins (pre-S1, pre-S2, and S); and the X protein. Regulation of HBV transcription is under the control of four promoters (the core, pre-S1, pre-S2/S, and X promoters) and two enhancer regions (EN1 and EN2). Eight genotypes of HBV, designated A to H, have been determined, with some geographical distribution. The virus is non-cytopathic, with virus-specific cellular immunity being the main determinant for the outcome of exposure to HBV—acute infection with resolution of liver diseases within 6 months, or chronic HBV infection that is frequently associated with progressive liver injury. Detection of HBsAg in the serum, by conventional diagnostic immunoassays, is the key diagnostic marker for infection with HBV and persistent detection of HBsAg in serum for more than 6 months is the hallmark of chronic HBV infection. The best marker for clinically significant HBV replication is the level of HBV DNA in serum, as detected by sensitive polymerase chain reaction (PCR)-based assay. Worldwide more than 350 million people are chronically infected with HBV and are thus at increased risk of developing serious liver disease, such as chronic hepatitis, cirrhosis, liver failure and hepatocellular carcinoma (HCC).
The primary goal of treatment for chronic hepatitis B (CHB) is to permanently suppress HBV replication and prevent or improve liver disease. Seven drugs are currently available for treatment of CHB infection: conventional interferon, pegylated interferon and direct antiviral agents. The direct antivirals (nucleos/tide analogues) belong to three classes: L-nucleosides (lamivudine, telbivudine and emtricitabine); deoxyguanosine analogue (entecavir) and nucleoside phosphonates (adefovir and tenofovir), which directly interfere with HBV DNA replication, primarily as chain terminators. The key limitations for interferon treatment are major side effects, low rate of HBV DNA suppression and low rate of ALT normalization. The key limitations of the treatment with direct antivirals are development of resistance; rebound of HBV replication after stopping therapy, requiring prolonged, lifelong therapy; and very low rate of HBsAg clearance, increasing the risk of adverse events with prolonged, lifelong therapy. Importantly, current direct antivirals repress the reverse transcription of the pregenomic viral RNA into the genomic DNA. They thus act downstream to the formation of the cccDNA that is formed after virus entry into hepatocytes. cccDNA resides in the cell nucleus as additional minichromosomes that are transcribed into viral mRNAs and transmitted to daughter cells when hepatocytes divide. Current direct antivirals have no or very little effect on the HBV cccDNA reservoir and the expression of the viral genes. Thus, the currently available treatments are suboptimal and may be associated with severe side effects. Accordingly there is a need for better therapies to meet the treatment goals in HBV infection, in particular CHB infection. Indirectly acting antivirals (IAD), besides interferons, arise as a very promising alternative class of antivirals. Small molecules blocking the interaction of a cellular protein with a viral protein have been successfully developed to prevent HIV entry and HCV replication. Viral entry and innate immunity are obvious cellular functions to be screened for the identification of new therapeutic targets. However, unlike HIV and HCV, our knowledge of specific cellular functions used by HBV to replicate in hepatocytes remains very limited and systematic screening for the identification of these essential host factors is necessary to increase the diversity of potential therapeutic targets and molecules. A major goal is therefore to identify these functions for preventing their use and/or perturbation by the virus by safer and broad-spectrum molecules with high barrier to resistance.
Recent data strongly suggest that farnesoid X receptor (FXR), which is a member of the nuclear receptor superfamily, is implicated in the regulation of HBV core promoter activity and that bile acids could play an important role in the natural history of HBV infection (Ramiére C, Scholtés C, Diaz O, Icard V, Perrin-Cocon L, Trabaud M A, Lotteau V, André P. Transactivation of the hepatitis B virus core promoter by the nuclear receptor FXRalpha, Journal of Virology, 2008; 82: 10832-10840). Specifically, in the particular cellular model of infection in the Huh-7 cell line with various HBV infection vectors, data suggested that FXRα agonists increase viral replication while antagonists of FXRα may represent a new class of compounds useful for the treatment of HBV infection by inhibiting HBV replication.