# Herpes simplex virus 1 strain 17+ with R2 mutation in UL37 has residual retrograde transport

## TL;DR

This study shows that a specific mutation in HSV-1 does not fully stop the virus from moving backward in nerves, which has implications for vaccine development.

## Contribution

The study reveals that the R2 mutation in UL37 does not fully prevent retrograde transport in HSV-1 strain 17+.

## Key findings

- The R217 virus is highly attenuated in mice and acts as a potent vaccine.
- The R217 virus can establish latency and reactivate in mouse models of ocular and vaginal infection.
- The R2 mutation does not fully prevent retrograde transport of HSV-1 strain 17+.

## Abstract

Herpes simplex virus 1 (HSV-1) causes lifelong recurrent infections. Following primary infection of the oral or genital mucosa, HSV-1 travels retrogradely through axons and establishes latency in the cell body of ganglionic neurons of the peripheral nervous system. Periodic reactivation in neurons and anterograde transport of virions back to peripheral regions cause oral or genital ulcerations. Many host and viral factors implicated in retrograde and anterograde transport of HSV-1 have been identified. In particular, studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate retrograde transport of HSV-1 strain F. Here, we introduced the same R2 mutations in the highly neurovirulent HSV-1 strain 17+. We show that this R217 virus is highly attenuated in mice and acts as a potent vaccine that protects mice against acute HSV-1 infection. However, we report that the R217 virus has residual retrograde transport. We show that R217 can establish latency in mouse models of ocular and vaginal infection and reactivate. These results contradict published evidence and show that the R2 mutation is not sufficient to fully prevent retrograde transport of HSV-1.

Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen without a cure or vaccine. HSV-1 travels through nerves between the oral and genital mucosa and the peripheral nervous system, where it establishes lifelong latency. Studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate the retrograde transport of HSV-1 strain F from the mucosa to the nervous system. Here, we present contradictory findings. We report that an HSV-1 virus from strain 17+ with the same R2 mutation has residual retrograde transport. This shows that the R2 mutation is not sufficient to fully prevent the retrograde transport of HSV-1 in all settings. This finding may be particularly relevant for assessing the safety of prospective live-attenuated vaccines that include the R2 mutation.