Mutations within the pathogenic region of HSV-1 gK signal sequences alter cell surface expression and neurovirulence.

To investigate the role of the signal sequences of HSV-1 gK on virus replication and viral pathogenesis, we constructed recombinant viruses with and without mutations within the signal sequences of gK. These recombinant viruses expressed two additional copies of the mutated (MgK) or native form (NgK) of gK gene in place of the latency associated transcript (LAT) with a myc epitope tag, to facilitate detection, at their 3' end. The replication of MgK virus was similar to that of NgK both in vitro and in vivo as well as in the trigeminal ganglia (TG) of latently-infected mice. The levels of gB and gK transcripts in the corneas, TG, and brains of infected mice on days 3 and 5 post infection were markedly virus- and time-dependent as well as tissue-specific. Mutation in the signal sequence of gK in MgK virus blocked cell surface expression of gK-myc in rabbit skin (RS) cells, increased LD50 and decreased corneal scarring in ocularly infected mice as compared with the NgK or revertant (RgK) virus. MgK and NgK viruses and not the RgK virus had reduced extent of explant reactivation at the lower dose of ocular infection but not at the higher dose. However, time of reactivation was not affected by overexpression of the different forms of gK. Taken together, these results strongly suggest that the 8mer peptide (ITAYGLVL) within the signal sequence of gK promotes cell surface expression of gK in infected cells and ocular pathogenesis in infected mice.