Comparison of blocking HSV-1 gK interaction with signal peptide peptidase (SPP) in the eye versus trigeminal ganglia on virus replication, eye disease and latency-reactivation in HSV-1 ocularly infected mice

Abstract

Purpose : We previously reported that HSV-1 glycoprotein K (gK) is involve in exacerbation of eye disease in ocularly infected mice and global depletion of SPP using Tamoxifen inducible Cre mice significantly reduced HSV-1 replication in the eye and the level of latency and time of reactivation compared with control mice. Thus, the goal of this study was to determine the specific effect of SPP absence in trigeminal ganglia or eye on virus re[plication, eye disease and latency-reaction in ocularly infected mice.

Methods : We generated two SPP conditional knockout mice lacking SPP in their TG (i.e., Advil-SPP^-/-) or eye (i.e., Pax6-SPP^-/-), respectively. SPP conditional mice and WT (C57BL/6) mice were infected ocularly with 2 X 10⁵ PFU/eye of WT HSV-1 strain McKrae without corneal scarification. Virus replication in the eye and trigeminal ganglia (TG), survival, eye disease, and latency-reactivation were determined in infected mice.

Results : The absence of SPP in TG significantly reduced virus replication in the TG but not eye of ocularly infected mice compared with control mice, while the absence of SPP in the eye affected virus replication in both eyes and TG. Eye disease was significantly reduced in Pax6-SPP^-/- mice compared with Advil-SPP^-/- mice. Finally, absence of SPP in the eye did not affect the level of latency or time of reactivation, while level of latency and time of virus reactivation reduced in mice lacking SPP on their TG.

Conclusions : Overall, our results suggest that specific blocking of SPP in TG does not affect primary virus replication or eye disease but does reduce latency-reactivation, while absence of SPP in the eye affect primary virus replication and eye disease but does not reduce latency-reactivation. Thus, our results suggest that blocking of gK binding to SPP may represent a clinically effective and expedient target in developing HSV-1 therapeutics to reduce eye disease and reactivation.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.