ROLE OF MANNOSE-6-PHOSPHATE RECEPTORS IN HERPES-SIMPLEX VIRUS ENTRY INTO CELLS AND CELL-TO-CELL TRANSMISSION

Herpes simplex virus (HSV) glycoprotein D (gD) is essential for virus entry into cells, is modified with mannose-6-phosphate (M-6-P), and bi nds to both the 275-kDa M-6-P receptor (MPR) and the 46-kDa MPR (C. R. Brunetti, R. L. Burke, S. Kornfeld, W. Gregory, K. S. Dingwell, F. Ma siarz, and D. C. Johnson, J. Biol. Chem. 269:17067-17074, 1994). Since MPRs are found on the surfaces of mammalian cells,we tested the hypot hesis that MPRs could serve as receptors for HSV during virus entry in to cells. A soluble form of the 275-kDa MPR, derived from fetal bovine serum, inhibited HSV plaques on monkey Vero cells, as did polyclonal rabbit anti-MPR antibodies. In addition, the number and size of HSV pl aques were reduced when cells were treated with bovine serum albumin c onjugated with pentamannose-phosphate (PM-PO4-BSA), a bulky ligand whi ch can serve as a high-affinity ligand for MPRs. These data imply that HSV can use MPRs to enter cells; however, other molecules must also s erve as receptors for HSV because a reasonable fraction of virus could enter cells treated with even the highest concentrations of these inh ibitors. Consistent with the possibility that there are other receptor s, HSV produced the same number of plaques on MPR-deficient mouse fibr oblasts as were produced on normal mouse fibroblasts, but there was no inhibition with PM-PO4-BSA with either of these embryonic mouse cells . Together, these results demonstrate that HSV does not rely solely on MPRs to enter cells, although MPRs apparently play some role in virus entry into some cell types and, perhaps, act as one of a number of ce ll surface molecules that can facilitate entry. We also found that HSV produced small plaques on human fibroblasts derived from patients wit h pseudo-Hurler's polydystrophy, cells in which glycoproteins are not modified with M-6-P residues and yet production of infectious HSV part icles was not altered in the pseudo-Hurler cells. In addition, HSV pla que size was reduced by PM-PO4-BSA; therefore, it appears that M-6-P r esidues and MPRs are required for efficient transmission of HSV betwee n cells, a process which differs in some respects from entry of exogen ous virus particles.