A spliced latency-associated VZV transcript maps antisense to the viral transactivator gene 61

Area of Science:

• Virology
• Neuroscience
• Molecular Biology

Background:

• Varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, establishes lifelong latency in human neurons.
• Reactivation of VZV causes shingles, pain, and stroke, but the mechanisms of VZV latency are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying VZV latency in human trigeminal ganglia (TG).
• To identify specific viral transcripts involved in maintaining VZV latency.

Main Methods:

• Ultra-deep, virus-enriched RNA sequencing of latently infected human TG.
• Analysis of VZV mRNA expression, focusing on antisense transcripts.
• In vitro studies using co-transfection assays to assess gene suppression.
• Analysis of VLT isoform expression in lytic versus latent infection.

Main Results:

• Consistent expression of a spliced VZV mRNA, antisense to ORF61, termed VZV latency-associated transcript (VLT), was detected in human TG neurons.
• A unique VLT isoform predominates during VZV latency and specifically suppresses ORF61 gene expression.
• Multiple VLT isoforms (VLTly) are expressed during lytic infection, contrasting with the single predominant isoform in latency.

Conclusions:

• The VLT, particularly a unique isoform, plays a critical role in maintaining VZV latency by suppressing viral gene expression, specifically ORF61.
• This discovery links VZV latency mechanisms to other neurotropic alphaherpesviruses.
• Understanding VLT function provides novel insights into VZV latency and reactivation, potentially informing therapeutic strategies for VZV-associated diseases.