Co-replication analyses of naturally occurring defective hepatitis B virus variants with wild-type

Complex hepatitis B virus (HBV) variants with mutations in core promoter (Cp) plus deletions in the C gene and/or preS region – that are associated with development of liver cirrhosis in renal transplant recipients – show a drastically changed phenotype with altered transcription and disturbed surface and core protein expression. Here, we analyzed the replication phenotype of six different defective variant genomes, isolated from two patients, after co-transfection with HBV wild-type (wt) in varying proportions. Both in HuH7 and HepG2 cells, the variants showed enhanced replication and enrichment in the different transfected variant-wt mixtures. Contrary to artificial variants with only C gene deletions in wt context, the original complex variants as well as wt genomes carrying C gene and Cp mutations of the variants did mostly not suppress wt replication. Thus, the Cp mutations compensate the suppression of wt by C gene deletions and furthermore enhance the replication level.