The egress of herpesviruses from cells: the unanswered questions.

The presence of herpes simplex virus (HSV) capsids attached to invaginated cytoplasmic vesicles led Stackpole (15) to propose that capsids undergo envelopment at the inner nuclear membrane, de-envelopment at the outer nuclear membrane, and finally reenvelopment at cytoplasmic membranes. Over the years this model attracted numerous adherents principally on the basis of evidence that the extracellular virions lack proteins present in intracellular virions accumulating in the perinuclear space (11, 14). An alternative hypothesis was recently presented by Wild et al. (17) on the basis of the observation that nuclear pores become grossly enlarged in cells infected with wild-type virus. Two hypotheses have emerged. The first is that HSV virions undergo envelopment at the inner nuclear membrane, de-envelopment at the outer nuclear membrane or extensions thereof, and reenvelopment in cytoplasmic organelles (double envelopment model). The second hypothesis is that virions mature and egress the cell via two pathways. A minority, primarily early in infection, becomes enveloped at the inner nuclear membrane and is transported in vesicles to the extracellular space. The majority enters the cytoplasm late in infection through enlarged nuclear pores and becomes enveloped at cytoplasmic membranes, mainly Golgi and post-Golgi. Challenges to existing theories are the fabric of science, and no other recent controversy has generated as much discussion as the challenge to the double envelopment hypothesis. The letter by Mettenleiter and Minson and the response by Wild (10) sustain the respective models but do not define the problems associated with each model or the data necessary to reaffirm or reject them.