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Hepatitis B virus (HBV) codes for three forms of surface protein. The minor, large form is translated from transcripts specified by the preS1 promoter, while the middle and small forms are translated from transcripts specified by the downstream S promoter. When the large surface protein is overexpressed, the secretion of both subviral and virion particles is blocked within the secretory pathway. We show here that overexpression of the large surface protein leads to up to a 10-fold activation of the S promoter but not of an unrelated promoter. Neither the middle nor the small surface protein, nor a secretable form of the large surface protein, activates the S promoter, but agents that induce endoplasmic reticulum (ER) stress have an effect similar to that of the large surface protein. The large surface protein also activates the S promoter in the context of the entire viral genome. Therefore, it appears that HBV has evolved a feedback mechanism, such that ER stress induced by accumulation of the large surface protein increases the synthesis of the middle and small surface proteins, which in combination with the large surface protein can form mixed, secretable particles. In addition, like other agents that induce ER stress, the large surface protein can activate the cellular grp78 and grp94 promoters, raising the possibility that it may alter the physiology of the host cell.