Revision 1 : JVI 02592 - 07 1 Mechanisms of Varicella - Zoster Virus Neuropathogenesis in Human Dorsal Root Ganglia

2 Varicella-zoster virus (VZV) is a human alphaherpesvirus that infects sensory ganglia 3 and reactivates from latency to cause herpes zoster. VZV replication was examined in human 4 dorsal root ganglia (DRG) xenografts in mice with severe combined immunodeficiency using 5 multiscale correlative immunofluorescence and electron microscopy (IF-EM). These 6 experiments showed the presence of VZV genomic DNA, viral proteins and virion production in 7 both neurons and satellite cells within DRG. Furthermore, the multiscale analysis of VZV-host 8 cell interactions revealed virus-induced cell-cell fusion and polykaryon formation between 9 neurons and satellite cells during VZV replication in DRG in vivo. Satellite cell infection and 10 polykaryon formation in neuron-satellite cell complexes provide mechanisms to amplify VZV 11 entry into neuronal cell bodies, which is necessary for VZV transfer to skin in the affected 12 dermatome during herpes zoster. These mechanisms of VZV neuropathogenesis help to account 13 for the often severe neurologic consequences of herpes zoster. 14 15 Introduction 16 Varicella zoster virus (VZV) is a human neurotropic alphaherpesvirus with a linear DNA 17 genome that has at least 70 open reading frames (ORFs) encoding viral proteins (4). VZV 18 causes varicella during primary infection, establishes latency in sensory ganglia and may 19 reactivate to cause herpes zoster (4, 12). VZV persistence in cranial nerve and dorsal root sensory 20 ganglia appears to be a consistent consequence of primary VZV infection (4, 5, 12, 31). VZV is 21 related to herpes simplex virus (HSV) 1 and 2, which are also neurotropic human 22 alphaherpesviruses that establish latency in sensory ganglia, but in contrast to VZV, HSV 23 AC CE PT ED on Jauary 9, 2018 by gest http/jvi.asm .rg/ D ow nladed fom