THE ENTRY INHIBITOR MYRCLUDEX-B EFFICIENTLY BLOCKS VIRAL SPREADING IN VIVO IN HUMAN LIVER CHIMERIC uPA/ SCID MICE PREVIOUSLY INFECTED WITH HEPATITIS B VIRUS
Antiviral treatments based on interferon-a or polymerase inhibitors are generally notcurative and additional therapeutic strategies interfering with other HBV replicationsteps are needed. We previously demonstrated prevention of de novo HBV infectionby pre-treating uPA/SCID mice with Myrcludex-B, a lipopeptide derived from the HBVpreS1 domain (Nat. Biotech.2008). Aim of this study was to investigate the abilityof Myrcludex-B to block HBV spreading post-infection. Experimental design: humanchimeric uPA/SCID mice were injected with HBV-infectious serum (5×10E7 HBV DNAcopies/mouse). Treatment with Myrcludex-B (2mg/Kg/day; s.c. injection) was initiatedeither 3 days (group A, n=8) or 3 weeks (group B, n=7) post infection (p.i.). After 6 weeksof treatment, mice were analyzed serologically (HBV-DNA, HBsAg), intrahepaticallyby qRT-PCR (rcDNA, cccDNA) and by immunohistochemistry (HBcAg). Results: Myrcludex-B administration initiated 3-days p.i. efficiently prevented viral spreadingfrom the few initially infected human hepatocytes (HBcAg-positive cells). Six weekspost-treatment viremia and HBsAg levels remained low (<10E5 HBV-DNA/ml and<10 IU/ml, respectively), while in untreated mice median viremia increased to 3×10E7and the majority of human hepatocytes stained HBcAg-positive. Myrcludex-B blockedefficiently HBV spreading also when treatment was started 3-weeks p.i., in micedisplaying already median 3×10E6 HBV-DNA/ml. Even in this experimental setting,viremia and HBsAg levels were not significantly increased after 6 weeks of treatment(9 weeks p.i.) and median cccDNA loads remained 50-fold lower as controls andcomparable to values found at week 3 p.i. (0.02 copies/cell). Conclusions: Applicationof Myrcludex-B post HBV-infection showed strong capacities to block viral spreadingin vivo, suggesting that HBV preferentially disseminates via secreted virions and theuse of Myrcludex-B in combination with current HBV-drugs may improve patients’outcome.
HBV - Myrcludex-B - entry inhibitor - uPA/SCID