Non-neuronal sites of latency for alphaherpesviruses.

Alphaherpesvirinae subfamily members are widespread pathogens that cause a range of significant human and animal diseases, from mild mucocutaneous lesions to severe neurological and neonatal infections. Following primary infection of the craniofacial or genital mucosa, lytic replication occurs in epithelial cells, resulting in the production of infectious virus. Virus shed from infected epithelial cells inevitably encounters and enters sensory nerve termini innervating these tissues, after which it is transported to sensory neurons in trigeminal ganglia. Here, lytic viral replication subsides, and the viral genome transitions into a transcriptionally silent, histone-associated state maintained as heterochromatin. The only viral gene abundantly expressed in sensory neurons is the latency-associated transcript (LAT), which encodes several microRNAs and other non-coding RNAs. Alphaherpesvirus reactivation from latency is triggered by various stressors, including the synthetic corticosteroid dexamethasone, and emerging evidence revealed bovine-herpesvirus 1 (BoHV-1) and HSV-1 genomes persist in non-neuronal cells from latently infected animals. Immune cell subsets in the pharyngeal tonsil and/or lymphoid tissues harbor viral genomes and support stress-induced viral reactivation, suggesting these cells are latently infected. However, distinguishing true 'latency' from abortive or persistent infections in the human alphaherpesviruses remains challenging. Future studies leveraging single-cell transcriptomics, spatial profiling, and physiologically relevant animal and tissue culture models are critical for understanding the roles of non-neuronal reservoirs in herpesvirus pathogenesis. This knowledge will advance the understanding of latency, reactivation, and viral transmission, ultimately identifying novel antiviral strategies that reduce recurrent disease.