Differential requirement for cell fusion and virion formation in the pathogenesis of varicella-zoster virus infection in skin and T cells.
The protein product of varicella-zoster virus (VZV) ORF47 is a serine/threonine protein kinase and tegument component. Evaluation of two recombinants of the Oka strain, rOka47DeltaC, with a C-terminal truncation of ORF47, and rOka47D-N, with a point mutation in the conserved kinase motif, showed that ORF47 kinase function was necessary for optimal VZV replication in human skin xenografts in SCID mice but not in cultured cells. We now demonstrate that rOka47DeltaC and rOka47D-N mutants do not infect human T-cell xenografts. Differences in the growth of kinase-defective ORF47 mutants allowed an examination of requirements for VZV pathogenesis in skin and T cells in vivo. Although virion assembly was reduced and no virion transport to cell surfaces was observed, epidermal cell fusion persisted, and VZV polykaryocytes were generated by rOka47DeltaC and rOka47D-N in skin. Virion assembly was also impaired in vitro, but VZV-induced cell fusion continued to cause syncytia in cultured cells infected with rOka47DeltaC or rOka47D-N. Intracellular trafficking of envelope glycoprotein E and the ORF47 and IE62 proteins, components of the tegument, was aberrant without ORF47 kinase activity. In summary, normal VZV virion assembly appears to require ORF47 kinase function. Cell fusion was induced by ORF47 mutants in skin, and cell-cell spread occurred even though virion formation was deficient. VZV-infected T cells do not undergo cell fusion, and impaired virion assembly by ORF47 mutants was associated with a complete elimination of T-cell infectivity. These observations suggest a differential requirement for cell fusion and virion formation in the pathogenesis of VZV infection in skin and T cells.
Besser
Jaya
J
Stanford University, Department of Pediatrics, 300 Pasteur Dr., G-311, Stanford, CA 94305-5208, USA.
Ikoma
Minako
M
Fabel
Konstanze
K
Sommer
Marvin H
MH
Zerboni
Leigh
L
Grose
Charles
C
Arvin
Ann M
AM
D000818:Animals; D014645:Herpesvirus 3, Human / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D008561:Membrane Fusion; D051379:Mice; D011494:Protein Kinases / Q000502:physiology; D012867:Skin / Q000821:virology*; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000821:virology*; D014183:Transplantation, Heterologous; D014759:Viral Envelope Proteins / Q000502:physiology; D014771:Virion / Q000502:physiology*; D014779:Virus Replication
D014759:Viral Envelope Proteins; C056913:glycoprotein E, varicella-zoster virus; D011494:Protein Kinases; C085818:Varicella-Zoster ORF47-associated protein kinase