Herpes simplex virus type 1 latency-associated transcript gene promotes neuronal survival.

Area of Science:

• Neurovirology
• Molecular Virology
• Infectious Diseases

Background:

• Herpes simplex virus type 1 (HSV-1) establishes a complex relationship with the host's peripheral nervous system (PNS), including sensory neurons.
• HSV-1 can replicate in sensory neurons and also enter a latent state, but the regulatory mechanisms are not fully understood.
• The latency-associated transcript (LAT) is crucial for establishing HSV-1 latency, required for over 65% of latent infections.

Purpose of the Study:

• To investigate the function of the LAT gene in HSV-1 latency and its interaction with sensory neurons.
• To determine if LAT plays a role in preventing neuronal death during HSV-1 infection.
• To elucidate the role of LAT in the establishment and maintenance of viral latency in the PNS.

Main Methods:

• Generation of a 1.9-kb LAT deletion mutant in HSV-1 strain 17syn+.
• Analysis of wild-type, LAT deletion mutants, and rescued variants in a mouse ocular model.
• Quantification of latent infection sites in trigeminal ganglion (TG) neurons using single-cell quantitative PCR.
• Assessment of TG neuron loss and apoptosis using histological and TUNEL assays.

Main Results:

• LAT null mutants established approximately 75% fewer latent infections compared to wild-type or rescued virus.
• Infection with LAT mutants led to a significant increase in TG neuron loss (over 50%) compared to wild-type infection.
• The observed neuron death was not attributed to increased apoptosis.
• Animals infected with LAT mutants showed less frequent in vivo viral reactivation.

Conclusions:

• The HSV-1 LAT locus is essential for protecting sensory neurons from destruction during infection.
• LAT plays a critical role in enhancing the establishment of viral latency in the PNS by preventing neuronal loss.
• This study demonstrates a novel neuroprotective function of the LAT gene in HSV-1 pathogenesis.