ATTENUATION OF THE VACCINE OKA STRAIN OF VARICELLA-ZOSTER VIRUS AND ROLE OF GLYCOPROTEIN-C IN ALPHAHERPESVIRUS VIRULENCE DEMONSTRATED IN THE SCID-HU MOUSE

The SCID-hu mouse implanted with human fetal tissue is a novel model f or investigating human viral pathogenesis. Infection of human skin imp lants was used to investigate the basis for the clinical attenuation o f the varicella-zoster virus (VZV) strain, V-Oka, from which the newly licensed vaccine is made, The pathogenicity of V-Oka was compared wit h that of its parent, P-Oka, another low-passage clinical isolate, str ain 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 t hese VZV strains replicated well in tissue culture, only low-passage c linical isolates were fully virulent in skin, as shown by infectious v irus yields and analysis of implant tissues for VZV DNA and viral prot ein synthesis, The infectivity of V-Oka in skin was impaired compared to that of P-Oka, providing the first evidence of a virologic basis fo r the clinical attenuation of V-Oka. The infectivity of V-Oka was furt her 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 H SV-I disease, VZV caused extensive infection of epidermal and dermal s kin 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 t hymus/liver implants, but HSV-I was detected only in epithelial cells, with no evidence of lymphotropism. These SCID-hu mouse experiments sh ow that the clinical attenuation of the varicella vaccine can be attri buted to decreased replication of V-Oka in skin and that tissue cultur e passage alone reduces the ability of VZV to infect human skin in viv o. Furthermore, gC, which is dispensable for replication in tissue cul ture, plays a critical role in the virulence of the human alphaherpesv iruses VZV and HSV-1 for human skin.