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Glycoprotein L sets the neutralization profile of murid herpesvirus-4

University of Cambridge

¹ E-mail: pgs27{at}cam.ac.uk

Antibodies readily neutralize acute, epidemic viruses, but are less effective against more indolent pathogens such Herpesviruses. Murid Herpesvirus-4 (MuHV-4) provides an accessible model for tracking the fate of antibody-exposed gamma-herpes virions. Glycoprotein L (gL) plays a central role in MuHV-4 entry: it allows gH to bind heparan sulfate and regulates fusion-associated conformation changes in gH and gB. However, gL is non-essential: heparan sulfate binding can also occur via gp70, and the gB/gH complex alone seems to be sufficient for membrane fusion. Here we asked how gL affects the susceptibility of MuHV-4 to neutralization. Immune sera neutralized gL- virions more readily than gL+, chiefly because heparan sulfate binding now depended on gp70 and was therefore easier to block. But there were also post-binding effects. First, the down-stream, gL-independent conformation of gH became a neutralization target; gL normally prevents this by holding gH in an antigenically distinct heterodimer until after endocytosis. Second, gL- virions were more vulnerable to gB-directed neutralization. This covered multiple epitopes, and thus seemed to reflect a general opening up of the gH/gB entry complex that gL again normally restricts to late endosomes. gL therefore limits MuHV-4 neutralization by providing redundancy in cell binding and by keeping key elements of the virion fusion machinery hidden until after endocytosis.

Received 11 November 2008; accepted 19 January 2009.

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