The research in my laboratory is aimed to ascertain molecular mechanism of HBV/HDV infection with emphasis on pathogenesis. The goal of the first ongoing study is to understand how the virus-induced pathogenesis is linked to a particular genotype of HBV. Data available strongly indicate that infection with different HBV genotypes can lead to substantially different levels of liver damage and corresponding progression of the disease. We plan to compare aspects of replication, assembly, and also infectivity in primary human hepatocytes (PHH) and certain determinants of the host response for all known 8 HBV genotypes. The finding of the most infectious HBV genotype will be of significant importance to the HBV field. It has a great potential for three major applications. The peptides derived from the N-terminus of the PreS1 domain of the large envelope protein, which belongs to the more infectious genotype, would be more potent antiviral inhibitors, more efficiently interacting with the receptor(s) and preventing HBV and HDV spread. If the more infectious genotype displayed the ability to infect the majority of PHH, than it would be possible to conduct the microarray studies using the in vitro infection system of PHH and examine the host response. Such studies now are not feasible, since currently in a best situation only about 20% of hepatocytes can be infected. The use of the more infectious HBV genotype can also result in the establishment of HBV-susceptible cell lines. This will seriously reduce the need for primary human hepatocytes, which so far represent the most adequate cells susceptible to HBV infection. Overall, this study will: (i) facilitate the understanding of the molecular mechanism of HBV genotype-specific pathogenesis; (ii) have a serious impact on the understanding of virus-host interactions; (iii) have the potential to advance the development of new generation of anti-HBV antiviral peptides.