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-␥. 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. Varicella-zoster virus (VZV)is an alphaherpesvirus that causes chicken pox, or varicella, establishes lifelong latency in the sensory ganglia, and later reactivates to cause shingles, or herpes zoster. The pathogenesis of primary VZV infection is characterized by inoculation of respiratory mucosa, followed by a cell-associated viremia and a subsequent vesicular rash that develops 10 to 21 days after exposure (3). T cells appear to be a major target cell for VZV viremia. The virus infects primary human T cells in vitro and exhibits tropism for T cells in thymus/liver xenografts in the severe combined immunodeficiency (SCID)-hu mouse model in vivo (28,35,49). VZV alters cellular gene expression in T cells, as shown by downregulation of major histocompatibility (MHC) class I protein expression and microarray analysis of gene transcription (1, 18). Importantly, T cells have the capacity to transport infectious VZV through the circulation, resulting in the formation of typical cutaneous lesions in SCID-hu skin xenografts (29). The goal of these experiments was to further investigate the T-cell tropism of VZV by examining virion formation, effects on apoptotic and interferon (IFN) pathways in human T cells, and the contributions of the ORF66 protein to these processes, based on previous evidence that preventing ORF66 protein expression decreased VZV virulence in T-cell xenografts in vivo (37).The putative early gene ORF66 encodes a 47-kDa protein that localizes to both nuclei and cytoplasm of infected cells in vitro and is present in the VZV virion (22,50). Sequence analysis has revealed that ORF66 is highly homologous to serine/threonine protein kinases in other...

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