T-cell tropism and the role of ORF66 protein in pathogenesis of varicella-zoster virus infection.
The pathogenesis of varicella-zoster virus (VZV) involves a cell-associated viremia during which infectious virus is carried from sites of respiratory mucosal inoculation to the skin. We now demonstrate that VZV infection of T cells is associated with robust virion production and modulation of the apoptosis and interferon pathways within these cells. The VZV serine/threonine protein kinase encoded by ORF66 is essential for the efficient replication of VZV in T cells. Preventing ORF66 protein expression by stop codon insertion (pOka66S) impaired the growth of the parent Oka (pOka) strain in T cells in SCID-hu T-cell xenografts in vivo and reduced formation of VZV virions. The lack of ORF66 protein also increased the susceptibility of infected T cells to apoptosis and reduced the capacity of the virus to interfere with induction of the interferon (IFN) signaling pathway following exposure to IFN-gamma. However, preventing ORF66 protein expression only slightly reduced growth in melanoma cells in culture and did not diminish virion formation in these cells. The pOka66S virus showed only a slight defect in growth in SCID-hu skin implants compared with intact pOka. These observations suggest that the ORF66 kinase plays a unique role during infection of T cells and supports VZV T-cell tropism by contributing to immune evasion and enhancing survival of infected T cells.
Schaap
Anne
A
Department of Pediatrics, Stanford University School of Medicine, CA 94305-5208, USA. aschaap@stanford.edu
Fortin
Jean-Francois
JF
Sommer
Marvin
M
Zerboni
Leigh
L
Stamatis
Shaye
S
Ku
Chia-Chi
CC
Nolan
Garry P
GP
Arvin
Ann M
AM
D000818:Animals; D002478:Cells, Cultured; D006562:Herpes Zoster / Q000821:virology*; D014645:Herpesvirus 3, Human / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016366:Open Reading Frames; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D013601:T-Lymphocytes / Q000821:virology; D014774:Virulence; D014779:Virus Replication
D017346:Protein Serine-Threonine Kinases