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Journal of Virology, April 2006, p. 3592-3606, Vol. 80, No. 7
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.7.3592-3606.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus Type 1 Accumulation, Envelopment, and Exit in Growth Cones and Varicosities in Mid-Distal Regions of Axons

Monica Miranda Saksena,¹ Hiroyuki Wakisaka,^1, Bibing Tijono,¹ Ross A. Boadle,² Frazer Rixon,³ Hirotaka Takahashi,^1, and Anthony L. Cunningham^1*

Centre for Virus Research, Westmead Millennium Institute, Westmead Hospital, P.O. Box 412, Westmead, NSW 2145, and The University of Sydney, Sydney, Australia,¹ Electron Microscope Laboratory, ICPMR, Westmead Hospital, Westmead, NSW 2145, Australia,² MRC Virology unit, Institute of Virology, Church Street, Glasgow G11 5JR, United Kingdom³

Received 1 September 2005/ Accepted 9 January 2006

The mechanism of anterograde transport of alphaherpesviruses in axons remains controversial. This study examined the transport, assembly, and egress of herpes simplex virus type 1 (HSV-1) in mid- and distal axons of infected explanted human fetal dorsal root ganglia using confocal microscopy and transmission electron microscopy (TEM) at 19, 24, and 48 h postinfection (p.i.). Confocal-microscopy studies showed that although capsid (VP5) and tegument (UL37) proteins were not uniformly present in axons until 24 h p.i., they colocalized with envelope (gG) proteins in axonal varicosities and in growth cones at 24 and 48 h p.i. TEM of longitudinal sections of axons in situ showed enveloped and unenveloped capsids in the axonal varicosities and growth cones, whereas in the midregion of the axons, predominantly unenveloped capsids were observed. Partially enveloped capsids, apparently budding into vesicles, were observed in axonal varicosities and growth cones, but not during viral attachment and entry into axons. Tegument proteins (VP22) were found associated with vesicles in growth cones, either alone or together with envelope (gD) proteins, by transmission immunoelectron microscopy. Extracellular virions were observed adjacent to axonal varicosities and growth cones, with some virions observed in crescent-shaped invaginations of the axonal plasma membrane, suggesting exit at these sites. These findings suggest that varicosities and growth cones are probable sites of HSV-1 envelopment of at least a proportion of virions in the mid- to distal axon. Envelopment probably occurs by budding of capsids into vesicles with associated tegument and envelope proteins. Virions appear to exit from these sites by exocytosis.

Present address: Department of Otolaryngology, Ehime University, Shizkawa, Toon-City, Ehime, Japan 791-0295.

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