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J Virol, February 1998, p. 965-974, Vol. 72, No. 2
Department of Pediatrics, Stanford University
School of Medicine, Stanford, California 943051;
Department of Ophthalmology, University of Pittsburgh,
Pittsburgh, Pennsylvania 152132;
Department of Pediatrics, University of Iowa, Iowa City,
Iowa 522423; and
SyStemix, Inc., Palo
Alto, California 943044
Received 22 August 1997/Accepted 4 November 1997
The SCID-hu mouse implanted with human fetal tissue is a novel
model for investigating human viral pathogenesis. Infection of human
skin implants was used to investigate the basis for the clinical
attenuation of the varicella-zoster virus (VZV) strain, V-Oka, from
which the newly licensed vaccine is made. The pathogenicity of V-Oka
was compared with that of its parent, P-Oka, another low-passage
clinical isolate, strain Schenke (VZV-S), and VZV-Ellen, a standard
laboratory strain. The role of glycoprotein C (gC) in infectivity for
human skin was assessed by using gC-negative mutants of V-Oka and
VZV-Ellen. Whereas all of these VZV strains replicated well in tissue
culture, only low-passage clinical isolates were fully virulent in
skin, as shown by infectious virus yields and analysis of implant
tissues for VZV DNA and viral protein synthesis. The infectivity of
V-Oka in skin was impaired compared to that of P-Oka, providing the
first evidence of a virologic basis for the clinical attenuation of
V-Oka. The infectivity of V-Oka was further diminished in the absence
of gC expression. All strains except gC-Ellen retained some capacity to
replicate in human skin, but cell-free virus was recovered only from
implants infected with P-Oka or VZV-S. Although VZV is closely related to herpes simplex virus type 1 (HSV-1) genetically, experiments in the
SCID-hu model revealed differences in tropism for human cells that
correlated with differences in VZV and HSV-1 disease. VZV caused
extensive infection of epidermal and dermal skin cells, while HSV-1
produced small, superficial lesions restricted to the epidermis. As in
VZV, gC expression was a determinant for viral replication in skin. VZV
infects human CD4+ and CD8+ T cells in
thymus/liver implants, but HSV-1 was detected only in epithelial cells,
with no evidence of lymphotropism. These SCID-hu mouse experiments show
that the clinical attenuation of the varicella vaccine can be
attributed to decreased replication of V-Oka in skin and that tissue
culture passage alone reduces the ability of VZV to infect human skin
in vivo. Furthermore, gC, which is dispensable for replication in
tissue culture, plays a critical role in the virulence of the human
alphaherpesviruses VZV and HSV-1 for human skin.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Attenuation of the Vaccine Oka Strain of
Varicella-Zoster Virus and Role of Glycoprotein C in Alphaherpesvirus
Virulence Demonstrated in the SCID-hu Mouse
*
Corresponding author. Mailing address: Department
of Pediatrics, Stanford University School of Medicine, Stanford, CA
94305-5208. Phone: (650) 723-5682. Fax: (650) 725-8040. E-mail:
arvinam{at}leland.stanford.edu.
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