Cd8+ T Cells Can Block Herpes Simplex Virus Type 1 (HSV-1) Reactivation from Latency in Sensory Neurons

TLDR

Recurrent herpes simplex virus type 1 disease usually results from reactivation of latent virus in sensory neurons and transmission to peripheral sites. The study aims to define mechanisms that maintain HSV‑1 latency in sensory neurons and proposes that compromised neuronal inhibition of reactivation triggers immediate‑early/early protein expression that activates CD8⁺ T cells to abort virion production. CD8⁺ T cells present in trigeminal ganglia were shown to maintain HSV‑1 latency in ex vivo cultures, and depletion of CD8⁺ cells with anti‑CD8α antibody induced reactivation, evidenced by late protein production and infectious virions. CD8⁺ T cells infiltrate and persist in trigeminal ganglia after primary infection, and their presence prevents HSV‑1 reactivation without killing neurons.

Abstract

Recurrent herpes simplex virus type 1 (HSV-1) disease usually results from reactivation of latent virus in sensory neurons and transmission to peripheral sites. Therefore, defining the mechanisms that maintain HSV-1 in a latent state in sensory neurons may provide new approaches to reducing susceptibility to recurrent herpetic disease. After primary HSV-1 corneal infection, CD8+ T cells infiltrate the trigeminal ganglia (TGs) of mice, and are retained in latently infected ganglia. Here we demonstrate that CD8+ T cells that are present in the TGs at the time of excision can maintain HSV-1 in a latent state in sensory neurons in ex vivo TG cultures. Latently infected neurons expressed viral genome and some expressed HSV-1 immediate early and early proteins, but did not produce HSV-1 late proteins or infectious virions. Addition of anti-CD8α monoclonal antibody 5 d after culture initiation induced HSV-1 reactivation, as demonstrated by production of viral late proteins and infectious virions. Thus, CD8+ T cells can prevent HSV-1 reactivation without destroying the infected neurons. We propose that when the intrinsic capacity of neurons to inhibit HSV-1 reactivation from latency is compromised, production of HSV-1 immediate early and early proteins might activate CD8+ T cells aborting virion production.