High conservation of herpes simplex virus UL5/UL52 helicase-primase complex in the era of new antiviral therapies

• HSV helicase-primase complex is a promising target for new antivirals.
• Identification of novel mutations accounting for the natural polymorphism of HSV helicase complex.
• No impact of HSV susceptibility to currently approved drugs on the natural polymorphism of HSV helicase-primase complex.
• Useful data for the monitoring of HSV genotypic resistance to HSV helicase-primase inhibitors.

The emergence of herpes simplex virus (HSV) resistance to current antiviral drugs, that all target the viral DNA polymerase, constitutes a major obstacle to antiviral treatment effectiveness of HSV infections, especially in immunocompromised patients. A novel and promising class of inhibitors of the HSV UL5/UL52 helicase-primase (HP) complex has been reported to hinder viral replication with a high potency. In this study, we describe the low natural polymorphism (interstrain identity >99.1% at both nucleotide and amino acid levels) of HSV HP complex subunits pUL5 and pUL52 among 64 HSV (32 HSV-1 and 32 HSV-2) clinical isolates, and we show that the HSV resistance profile to the first-line antiviral drug acyclovir (ACV) does not impact on the natural polymorphism of HSV HP complex. Genotypic tools and polymorphism data concerning HSV HP complex provided herein will be useful to detect drug resistance mutations in a relevant time frame when HP inhibitors (HPIs), i.e., amenamevir and pritelivir, will be available in medical practice.