Intracellular retention of surface protein by a hepatitis B virus mutant that releases virion particles.

In the course of chronic infection, hepatitis B virus mutants can sometimes be found circulating in the serum as the predominant species. One class of such mutants contains in-frame deletions in the S promoter region. By transfecting hepatoma cells with wild-type or mutant viral genomic DNA, we have shown that one such mutant gives rise to extremely small amounts of S transcripts, as expected, and therefore expresses very little of the middle and small surface (viral envelope) proteins that are translated from these transcripts. In addition, this mutant gives rise to greater-than-wild-type levels of the preS1 transcripts, which are translated into the large surface protein. Because the large surface protein, unlike the other forms of surface protein, is incompetent for secretion, cells transfected with the mutant viral DNA contain large amounts of 20-nm particles within dilated perinuclear vesicles. Therefore, this and similar S promoter mutants may be one contributing factor in the pathogenesis of ground-glass cells, which are hepatocytes containing nonsecretable viral surface proteins within dilated vesicles and are commonly found during chronic hepatitis B. Interestingly, DNA-containing virion particles are secreted into the medium by cells transfected with the mutant DNA, in amounts that are slightly larger than those secreted from wild-type-transfected cells, apparently because the amount of large surface protein is insufficient to block virion secretion. This finding may explain how such mutants can become the predominant circulating species in the serum, especially if there are selection pressures against the wild-type virus.