Herpes Simplex Virus-1 (HSV-1) establishes life-long latency in sensory neurons. Following reactivation, HSV-1 travels along axons and is released from axon termini into the epidermis, causing recurrent infections or asymptomatic shedding. Interferons (IFNs) present in herpes lesions limit viral replication in non-neuronal cells, however less is known about the role IFNs play in HSV-1 release from axons. We aim to define whether type I, II and III IFNs can inhibit HSV-1 release from axon termini of sensory neurons.
Primary sensory neurons were grown in 3-chamber neuron devices, compartmentalising cell bodies and axons, allowing separate treatment of the two compartments. Neuronal cell bodies were infected with HSV-1 and axons were treated with IFNα-1, α-14, β, γ or λ-3. Our results showed that axonal IFN treatment resulted in a marked reduction in virus release from axons following treatment with all three types of IFNs. Furthermore, we observed a greater inhibition with different IFNα subtypes with IFNα-14 showing greater inhibition compared to IFNα-1 (~90% and ~50% inhibition respectively). No axonal treatment altered viral replication or release from the cell bodies, or the transport of viral proteins along axons. Confocal analysis of STAT1 and STAT3 activation showed that IFNα and IFNγ activate STAT1/3 locally in axons, but only IFNγ produced a cell-wide response, with STAT1/3 observed in both cell bodies and axons. We have also shown for the first time that HSV-1 can activate STAT1/3 in neurons, in the absence of IFN.
We have shown for the first time that Type I, II and III IFNs can directly act on axons to inhibit HSV-1 release. As HSV-1 exit from sensory nerves is essential for virus spread, determining the effectiveness of IFN treatment in reducing HSV-1 exit may contribute to the development of novel long-lasting immunotherapy strategies for the control of recurrent herpes infection.