Molecular Biology Of Varicella Zoster Virus Infection

National Institute Of Allergy And Infectious Diseases

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Abstract

Varicella-zoster virus (VZV) establishes latency in human sensory and cranial nerve ganglia during primary infection (varicella), and the virus can reactivate and cause zoster after primary infection. The mechanism of how the virus infects and maintains latency and how it reactivates is poorly understood, largely due to the lack of robust models. Cellular proteins that phosphorylate other proteins, termed mitogen activated protein kinases (MAPKs) have been shown to play a role in VZV infection of non-neuronal cells and affect VZV infectivity in differing cell types. We used several human neuronal culture systems to investigate the role of one such MAPK, the c-Jun N-terminal kinase (JNK), in VZV lytic infection and reactivation in neurons. We found that the JNK pathway is specifically activated following infection of human embryonic stem cell-derived neurons, and that this activation of JNK is essential for efficient viral protein expression and replication. Inhibition of the JNK pathway blocked viral replication in a manner distinct from acyclovir, and an acyclovir resistant VZV isolate was as sensitive to the effects of JNK inhibition as an acyclovir sensitive VZV isolate in neurons. Moreover, in a human neuronal model of viral latency and reactivation, we found that inhibition of the JNK pathway resulted in a marked reduction in reactivation of VZV. Finally, we utilized a new technique to efficiently generate cells expressing markers of human sensory neurons from neural crest cells, and established a critical role for the JNK pathway in infection of these cells. In summary, the JNK pathway plays an important role in lytic infection and reactivation of VZV in physiologically relevant cell types, and may provide an alternative target for antiviral therapy.