The herpes simplex virus 1 UL51 gene product has cell type-specific functions in cell-to-cell spread.

UNLABELLED: The herpes simplex virus 1 (HSV-1) UL51 gene encodes a 244-amino-acid (aa) palmitoylated protein that is conserved in all herpesviruses. The alphaherpesvirus UL51 (pUL51) protein has been reported to function in nuclear egress and cytoplasmic envelopment. No complete deletion has been generated because of the overlap of the UL51 coding sequence 5' end with the UL52 promoter sequences, but partial deletions generated in HSV and pseudorabies virus (PrV) suggest an additional function in epithelial cell-to-cell spread. Here we show partial uncoupling of the replication, release, and cell-to-cell spread functions of HSV-1 pUL51 in two ways. Viruses in which aa 73 to 244 were deleted from pUL51 or in which a conserved YXXΦ motif near the N terminus was altered showed cell-specific defects in spread that cannot be accounted for by defects in replication and virus release. Also, a cell line that expresses C-terminally enhanced green fluorescent protein (EGFP)-tagged pUL51 supported normal virus replication and release into the medium but the formation of only small plaques. This cell line also failed to support normal localization of gE to cell junctions. gE and pUL51 partially colocalized in infected cells, and these two proteins could be coimmunoprecipitated from infected cells, suggesting that they can form a complex during infection. The cell-to-cell spread defect associated with the pUL51 mutation was more severe than that associated with gE-null virus, suggesting that pUL51 has gE-independent functions in epithelial cell spread. IMPORTANCE: Herpesviruses establish and reactivate from lifelong latency in their hosts. When they reactivate, they are able to spread within their hosts despite the presence of a potent immune response that includes neutralizing antibody. This ability is derived in part from a specialized mechanism for virus spread between cells. Cell-to-cell spread is a conserved property of herpesviruses that likely relies on conserved viral genes. An understanding of their function may aid in the design of vaccines and therapeutics. Here we show that one of the conserved viral genes, UL51, has an important role in cell-to-cell spread in addition to its previously demonstrated role in virus assembly. We find that its function depends on the type of cell that is infected, and we show that it interacts with and modulates the function of another viral spread factor, gE.