Selection of a secretion-incompetent mutant in the serum of a patient with severe hepatitis B.
OBJECTIVE
A secretion-incompetent, highly replicating hepatitis B variant was previously found as the dominant viral population in the serum of a liver transplant recipient with severe hepatitis B reinfection. The secretion block resulted from mutations in the S protein, including the Gly145Arg substitution known to emerge under antibody to hepatitis B surface antigen immunoglobulin treatment. Here we investigated the mechanisms that allow selection of a secretion-incompetent virus as the predominant strain in the serum.


METHODS
To reproduce the interaction of viral quasispecies occurring in vivo, cotransfection experiments were performed with full-length genomes containing wild-type or mutant sequences. In addition, the relevance of mutations in the common S part of the surface proteins for the competence of L and S protein to support viral secretion was studied.


RESULTS
A small amount of wild-type virus or of a wild-type S protein-expressing variant rescued secretion of the defective mutant. In the secreted virions, the high-replicating mutant genome was predominant. Selection of the defective mutant was further supported by a transdominant negative effect of mutant S protein on wild-type virion secretion. In contrast, mutant L protein with the same c-terminal mutations as mutant S protein efficiently supported virion formation and secretion.


CONCLUSIONS
Interaction of the variant with a small amount of wild-type virus can reverse its secretion-defective phenotype. Mutations in the common region of S and L protein have different consequences for the ability of the envelope proteins to support virion assembly and secretion.
D012634:Bodily Secretions / Q000821:virology*; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000378:metabolism / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D014759:Viral Envelope Proteins / Q000235:genetics; D014771:Virion / Q000235:genetics / Q000254:growth & development; D014779:Virus Replication / Q000235:genetics
C096362:L protein, hepatitis B virus; D014759:Viral Envelope Proteins