HSV-1 LAT promotes ocular diseases in the absence of type I IFN responses in sensory neurons

Type I interferons (IFNs) are a critical first line of antiviral defense during herpes simplex virus type 1 (HSV-1) infection. In mice, the type I IFN family includes at least 14 IFNα subtypes and a single IFNβ, each of which signals through the common receptor, IFNαβR. We previously reported that deletion of a single IFNα subtype (IFNα2A^-/-) alters HSV-1 latency levels following ocular infection without affecting viral reactivation. While the role of type 1 IFN in HSV-1 infection has been studied extensively, how IFN type 1 responses crosstalk with latency-associated transcript (LAT) in sensory neurons remains to be elucidated. To investigate the functional relationship between LAT and type I IFN signaling, specifically within neurons, we crossed Advillin-Cre mice with IFNAR1^flox/flox mice to generate sensory neuron-specific IFNAR1 knockout mice (Avil-IFNAR1^-/-). Following HSV-1 infection, the survival rate of Avil-IFNAR1^-/- mice was significantly lower than that of infected wild-type mice. However, unlike global IFNAR1 deficiency, there were no significant survival differences between LAT(+) and LAT(-) viral infection in Avil-IFNAR1^-/- mice. During acute infection, loss of type I IFN signaling in sensory neurons enhanced viral replication in the eye and trigeminal ganglia, but not in the tears of infected mice. During latency, sensory neuron-specific IFNAR1 deficiency increased gB DNA copy numbers in LAT(-)-infected mice to levels similar to those in LAT(+)-infected mice. LAT transcript levels in these mice were also markedly higher than those in wild-type mice. The absence of neuronal type 1 IFN signaling increased T-cell exhaustion and eye disease in infected mice. However, the absence of IFNAR1 did not affect reactivation in these mice. Collectively, these findings demonstrate that neuron-intrinsic type I IFN signaling plays a critical role in controlling ocular viral replication, limiting HSV-1-induced eye diseases, and modulating latency-associated viral and immune parameters.IMPORTANCEHSV-1 LAT plays an important role in latency reactivation, while type I interferon (IFN) regulates immune protection; the interaction of HSV-1 LAT with type I IFN influences virus infectivity in vivo. To investigate how LAT and IFNαβ affect the peripheral nervous system, we generated IFNAR1 conditional knockout mice using Advillin-Cre mice, which lack functional type 1 IFN signaling in the peripheral nervous system. The absence of interferon A receptor 1 (IFNAR1) in these infected mice led to enhanced viral replication in the eyes and trigeminal ganglia (TG), with increased ocular disease and T-cell exhaustion. However, viral titers in mouse tears and reactivation kinetics remained unchanged. In peripheral sensory neurons, the absence of IFNAR1 was associated with (i) similar gB DNA levels in TG of latently infected Avil-IFNAR1^-/- mice compared to control infected mice, (ii) LAT expression in Avil-IFNAR1^-/- mice was significantly elevated as compared with control infected mice, (iii) notably, IFNAR1 deficiency led to significantly more LAT-dependent eye disease in Avil-IFNAR1^-/--infected mice, and (iv) T-cell exhaustion was enhanced significantly in Avil-IFNAR1^-/--infected mice. These findings demonstrate that type I IFN signaling in sensory neurons restricts HSV-1 pathogenesis and modulates LAT expression without affecting reactivation.