Analysis of varicella zoster virus attenuation by evaluation of chimeric parent Oka/vaccine Oka recombinant viruses in skin xenografts in the SCIDhu mouse model.
Varicella-zoster virus (VZV) is the only human herpes virus for which a vaccine has been licensed. A clinical VZV isolate, designated the parent Oka (pOka) strain was passed in human and non-human fibroblasts to produce vaccine Oka (vOka). The pOka and vOka viruses exhibit similar infectivity in cultured cells but healthy susceptible individuals given vaccines derived from vOka rarely develop the cutaneous vesicular lesions characteristic of varicella. Inoculation of skin xenografts in the SCIDhu mouse model of VZV pathogenesis demonstrated that vOka had a reduced capacity to replicate in differentiated human epidermal cells in vivo (Moffat, J.F., Zerboni, L., Kinchington, P.R., Grose, C., Kaneshima, H., Arvin A.M., 1998a. Attenuation of the vaccine Oka strain of varicella-zoster virus and role of glycoprotein C in alphaherpesvirus virulence demonstrated in the SCID-hu mouse. J Virol. 72:965-74). In order to investigate the attenuation of vOka in skin, we made chimeric pOka and vOka recombinant viruses from VZV cosmids. Six chimeric pOka/vOka viruses were generated using cosmid sets that incorporate linear overlapping fragments of VZV DNA from cells infected with pOka or vOka. The cosmid sets consist of pOka and vOka DNA segments that have identical restriction sites. As expected, the growth kinetics and plaque morphologies of the six chimeric pOka/vOka viruses were indistinguishable in vitro. However, the chimeric viruses exhibited varying capacities to replicate when evaluated in skin xenografts in vivo. The presence of ORFs 30-55 from the pOka genome was sufficient to maintain wild-type infectivity in skin. Chimeric viruses containing different vOka components retained the attenuation phenotype, suggesting that vOka attenuation is multi-factorial and can be produced by genes from different regions of the vOka genome.
Zerboni
Leigh
L
Department of Pediatrics, S-356, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5208, USA. zerboni@stanford.edu
Hinchliffe
Stewart
S
Sommer
Marvin H
MH
Ito
Hideki
H
Besser
Jaya
J
Stamatis
Shaye
S
Cheng
Jason
J
Distefano
Daniel
D
Kraiouchkine
Nikolai
N
Shaw
Alan
A
Arvin
Ann M
AM
D000818:Animals; D006562:Herpes Zoster / Q000276:immunology / Q000821:virology*; D014645:Herpesvirus 3, Human / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011995:Recombination, Genetic; D012882:Skin Tests; D014183:Transplantation, Heterologous; D014613:Vaccines, Attenuated / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology; D014774:Virulence
D014613:Vaccines, Attenuated; D014765:Viral Vaccines