Axonal entry and retrograde transport define HSV-1 latency establishment and reactivation potential in neurons
- 1University of California Irvine, School of Medicine
Abstract
Herpes simplex virus 1 (HSV-1) establishes life-long latency in peripheral neurons following neuroinvasion, yet the early determinants governing latency versus productive infection remain poorly understood. Available in vitro models bypass the physiological route of infection by directly infecting neuronal cell bodies under antiviral suppression. Here, we established a compartmented axonal infection model that recapitulates HSV-1 neuroinvasion and latency establishment without pharmacological inhibitors. Using primary superior cervical ganglion (SCG) neurons, we demonstrated that low-dose axonal infection consistently establishes latency, whereas higher axonal doses or direct somatic infection led to productive replication. Latently infected neurons exhibit accumulation of the latency-associated transcript (LAT) and can be efficiently reactivated by UV-inactivated virus or VP16 expression. Remarkably, productive infection can be induced during low-dose axonal infection by simultaneous exposure of neuronal cell bodies, but not axons, to replication-deficient virions, implicating tegument delivery in soma overrides latency establishment. Conversely, excess replication-incompetent particles in axons suppress productive outcomes and subsequent reactivations, suggesting competition for retrograde transport. Together, these findings identify axonal entry and transport as critical regulatory checkpoints in HSV-1 latency establishment and suggest that interference with retrograde trafficking may represent a strategy to limit neuroinvasion and life-long reactivations.
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BibTeX
@misc{pantoja2026axonal,
title = {{Axonal entry and retrograde transport define HSV-1 latency establishment and reactivation potential in neurons}},
author = {C. Pantoja and A. D. D. Loaiza and K. T. Y. Luong and O. O. Koyuncu},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754144},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754144v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Axonal entry and retrograde transport define HSV-1 latency establishment and reactivation potential in neurons
AU - C. Pantoja
AU - A. D. D. Loaiza
AU - K. T. Y. Luong
AU - O. O. Koyuncu
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754144
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754144v1
AB - Herpes simplex virus 1 (HSV-1) establishes life-long latency in peripheral neurons following neuroinvasion, yet the early determinants governing latency versus productive infection remain poorly understood. Available in vitro models bypass the physiological route of infection by directly infecting neuronal cell bodies under antiviral suppression. Here, we established a compartmented axonal infection model that recapitulates HSV-1 neuroinvasion and latency establishment without pharmacological inhibitors. Using primary superior cervical ganglion (SCG) neurons, we demonstrated that low-dose axonal infection consistently establishes latency, whereas higher axonal doses or direct somatic infection led to productive replication. Latently infected neurons exhibit accumulation of the latency-associated transcript (LAT) and can be efficiently reactivated by UV-inactivated virus or VP16 expression. Remarkably, productive infection can be induced during low-dose axonal infection by simultaneous exposure of neuronal cell bodies, but not axons, to replication-deficient virions, implicating tegument delivery in soma overrides latency establishment. Conversely, excess replication-incompetent particles in axons suppress productive outcomes and subsequent reactivations, suggesting competition for retrograde transport. Together, these findings identify axonal entry and transport as critical regulatory checkpoints in HSV-1 latency establishment and suggest that interference with retrograde trafficking may represent a strategy to limit neuroinvasion and life-long reactivations.
ER -