Evaluation of novel strategies to combat hepatitis B virus targetting wild-type and drug-resistant mutants in experimental models.
Recent studies have shown that the kinetics of hepatitis B virus (HBV) clearance during antiviral therapy are slow, requiring long-term therapy to control viral replication. It has also been shown that emergence of resistant mutants is accelerated by high HBV replication and hepatocyte turnover, which are common features in patients with chronic HBV infection. It is therefore important to continue research on novel antiviral agents to design optimal combination strategies. The duck and woodchuck models of hepadnavirus infection are currently the best models for the investigation of the inhibitory effect of nucleoside analogues on wild-type and lamivudine-resistant mutants. Our studies revealed that these mutants have a decreased priming and elongation activity, and remain sensitive to novel nucleoside analogues. Tissue culture experiments with transient transfection of wild-type and mutant viruses also confirmed these data. Infection studies in primary hepatocytes and in animal models gave insight into the pathobiology of lamivudine-resistant mutants, as well as into the kinetics of wild-type virus clearance during antiviral therapy. Furthermore, it appears that novel strategies inducing a specific anti-HBV immune response by a DNA vaccine approach may induce viral clearance. Altogether, these results suggest that: (i) lamivudine-resistant mutants are likely to be cross-resistant to other L-cytidine analogues; (ii) antiviral therapy using a single reverse transcriptase (RT) inhibitor is likely to fail to eradicate viral covalently closed circular DNA; and (iii) new nucleoside analogues with unique mode of action (inhibition of priming or elongation of RT, or DNA polymerase activity) and activity against lamivudine-resistant strains are emerging. Combination of these new anti-HBV agents with DNA based immunization may prove useful to eradicate viral infection.
Zoulim
F
F
INSERM Unit 271, Lyon, France. zoulim@lyon151.inserm.fr
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004359:Drug Therapy, Combination; D006509:Hepatitis B / Q000188:drug therapy; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D009154:Mutation; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents