Differentiated SH-SY5Y cells as a model to study repression and de-repression of VZV

Varicella zoster virus (VZV) is a human-specific virus that during primary infection establishes latency in neurons. The only transcripts detected in infected human trigeminal ganglia obtained at short post-mortem interval correspond to the VZV latency-associated transcript (VLT) and fusion transcripts between VLT and open reading frame 63 (VLT-ORF63). In vitro studies showed that one of these fusion transcripts (VLT-ORF63-1) is translated into a protein (pVLT63) that induces reactivation. The mechanisms that lead to this restricted gene expression are not known, partly due to the difficulty of working with human neurons. We addressed whether the expandable neuroblastoma-derived cell line SH-SY5Y could serve as a model to investigate the mechanisms that lead to repression of VZV during establishment of latency. VZV productive infection of differentiated SH-SY5Y (dSH-SY5Y) in the presence of acyclovir (ACV) induced a progressive repression of the virus. This resulted in two marked phenotypes upon removal of ACV: release of repression leading to productive replication and complete repression resembling abortive infection. In contrast to what is found in human TG, the VZV transcription profiling showed low level genome-wide expression. However, a small percentage of dSH-SY5Y cells harboured the viral genome and VLT-containing transcripts for up to 20 days post infection. Exogenous expression of VLT-ORF63-1 induced productive infection. The model presented here could be employed to understand the mechanisms that lead to repression of the VZV genome prior to establishment of latency.