scholarly journals Varicella-Zoster Virus T Cell Tropism and the Pathogenesis of Skin Infection

2010 ◽  
pp. 189-209 ◽  
Author(s):  
Ann M. Arvin ◽  
Jennifer F. Moffat ◽  
Marvin Sommer ◽  
Stefan Oliver ◽  
Xibing Che ◽  
...  
Keyword(s):  
T Cell ◽  
Varicella Zoster Virus ◽  
Skin Infection ◽  
Cell Tropism ◽  
Varicella Zoster

scholarly journals ORF66 Protein Kinase Function Is Required for T-Cell Tropism of Varicella-Zoster Virus In Vivo

2006 ◽  
Vol 80 (23) ◽  
pp. 11806-11816 ◽  
Author(s):  
Anne Schaap-Nutt ◽  
Marvin Sommer ◽  
Xibing Che ◽  
Leigh Zerboni ◽  
Ann M. Arvin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Kinase ◽  
Varicella Zoster Virus ◽  
Kinase Domain ◽  
Cell Surface Expression ◽  
Cell Tropism ◽  
Varicella Zoster ◽  
Protein Functions

ABSTRACT Several functions have been attributed to the serine/threonine protein kinase encoded by open reading frame 66 (ORF66) of varicella-zoster virus (VZV), including modulation of the apoptosis and interferon pathways, down-regulation of major histocompatibility complex class I cell surface expression, and regulation of IE62 localization. The amino acid sequence of the ORF66 protein contains a recognizable conserved kinase domain. Point mutations were introduced into conserved protein kinase motifs to evaluate their importance to ORF66 protein functions. Two substitution mutants were generated, including a G102A substitution, which blocked autophosphorylation and altered IE62 localization, and an S250P substitution, which had no effect on either autophosphorylation or IE62 localization. Both kinase domain mutants grew to titers equivalent to recombinant parent Oka (pOka) in vitro. pOka66G102A had slightly reduced growth in skin, which was comparable to the reduction observed when ORF66 translation was prevented by stop codon insertions in pOka66S. In contrast, infection of T-cell xenografts with pOka66G102A was associated with a significant decrease in infectious virus production equivalent to the impaired T-cell tropism found with pOka66S infection of T-cell xenografts in vivo. Disrupting kinase activity with the G102A mutation did not alter IE62 cytoplasmic localization in VZV-infected T cells, suggesting that decreased T-cell tropism is due to other ORF66 protein functions. The G102A mutation reduced the antiapoptotic effects of VZV infection of T cells. These experiments indicate that the T-cell tropism of VZV depends upon intact ORF66 protein kinase function.

scholarly journals T-Cell Tropism and the Role of ORF66 Protein in Pathogenesis of Varicella-Zoster Virus Infection

2005 ◽  
Vol 79 (20) ◽  
pp. 12921-12933 ◽  
Author(s):  
Anne Schaap ◽  
Jean-Francois Fortin ◽  
Marvin Sommer ◽  
Leigh Zerboni ◽  
Shaye Stamatis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Expression ◽  
Varicella Zoster Virus ◽  
Stop Codon ◽  
Varicella Zoster Virus Infection ◽  
Cell Tropism ◽  
Varicella Zoster ◽  
Efficient Replication

ABSTRACT 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-γ. 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.

scholarly journals Analysis of T Cell Responses during Active Varicella-Zoster Virus Reactivation in Human Ganglia

2013 ◽  
Vol 88 (5) ◽  
pp. 2704-2716 ◽  
Author(s):  
M. Steain ◽  
J. P. Sutherland ◽  
M. Rodriguez ◽  
A. L. Cunningham ◽  
B. Slobedman ◽  
...  
Keyword(s):  
T Cell ◽  
Varicella Zoster Virus ◽  
T Cell Responses ◽  
Virus Reactivation ◽  
Varicella Zoster ◽  
Cell Responses

scholarly journals Studies on transfer of varicella-zoster-virus specific T-cell immunity from bone marrow donor to recipient

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 806-809 ◽  
Author(s):  
S Kato ◽  
H Yabe ◽  
M Yabe ◽  
M Kimura ◽  
M Ito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Varicella Zoster Virus ◽  
Cellular Immunity ◽  
Marrow Transplantation ◽  
T Cell Immunity ◽  
Lymphoproliferative Response ◽  
Varicella Zoster ◽  
Cell Immunity

Abstract The transfer of antigen-specific cellular immunity in human bone marrow transplantation (BMT) was studied in 49 donor-recipient pairs, using a varicella-zoster-virus (VZV) specific lymphoproliferative response (LPR) assay. Posttransplant VZV-LPR could be serially measured in 31 long-term surviving recipients. VZV-specific T-cell immunity was detected in the early posttransplant period in 4 of 16 recipients who were, and whose donors were, immune to VZV before BMT, but two of those positive responses diminished in the first 100 days posttransplant. No positive response was detected in the immediate posttransplant period when either only the recipient or the donor was immune to VZV pretransplant. Herpes zoster or chickenpox developed in the recipients depending on a history of pretransplant VZV infection when the VZV-LPR became negative, and recovery from VZV infection was always followed by quick conversion of VZV-LPR. Long-lasting positive VZV-LPR was observed in the two recipients who experienced VZV infection in the immediate pretransplant period and received marrow graft from an immune donor. Our results indicate that a simple or direct transfer of VZV-specific cellular immunity from a marrow donor to a recipient cannot be expected in usual clinical bone marrow transplantation and that there might be a collaboration or recruitment of immune responses involving both donor and recipient that permits the VZV-LPR to remain positive posttransplant.

scholarly journals Functions of the ORF9-to-ORF12 Gene Cluster in Varicella-Zoster Virus Replication and in the Pathogenesis of Skin Infection

2008 ◽  
Vol 82 (12) ◽  
pp. 5825-5834 ◽  
Author(s):  
Xibing Che ◽  
Mike Reichelt ◽  
Marvin H. Sommer ◽  
Jaya Rajamani ◽  
Leigh Zerboni ◽  
...  
Keyword(s):  
Varicella Zoster Virus ◽  
Gene Cluster ◽  
Skin Infection ◽  
Cultured Cells ◽  
Human Tonsil ◽  
Reading Frame ◽  
Varicella Zoster ◽  
The Individual

ABSTRACT The gene cluster composed of varicella-zoster virus (VZV) open reading frame 9 (ORF9) to ORF12 encodes four putative tegument proteins and is highly conserved in most alphaherpesviruses. In these experiments, the genes within this cluster were deleted from the VZV parent Oka (POKA) individually or in combination, and the consequences for VZV replication were evaluated with cultured cells in vitro and with human skin xenografts in SCID mice in vivo. As has been reported for ORF10, ORF11 and ORF12 were dispensable for VZV replication in melanoma and human embryonic fibroblast cells. In contrast, deletion of ORF9 was incompatible with the recovery of infectious virus. ORF9 localized to the virion tegument and formed complexes with glycoprotein E, which is an essential protein, in VZV-infected cells. Recombinants lacking ORF10 and ORF11 (POKAΔ10/11), ORF11 and ORF12 (POKAΔ11/12), or ORF10, ORF11 and ORF12 (POKAΔ10/11/12) were viable in cultured cells. Their growth kinetics did not differ from those of POKA, and nucleocapsid formation and virion assembly were not disrupted. In addition, these deletion mutants showed no differences compared to POKA in infectivity levels for primary human tonsil T cells. Deletion of ORF12 had no effect on skin infection, whereas replication of POKAΔ11, POKAΔ10/11, and POKAΔ11/12 was severely reduced, and no virus was recovered from skin xenografts inoculated with POKAΔ10/11/12. These results indicate that with the exception of ORF9, the individual genes within the ORF9-to-ORF12 gene cluster are dispensable and can be deleted simultaneously without any apparent effect on VZV replication in vitro but that the ORF10-to-ORF12 cluster is essential for VZV virulence in skin in vivo.

T-cell response against varicella-zoster virus in fingolimod-treated MS patients

Neurology ◽  
2013 ◽  
Vol 81 (2) ◽  
pp. 174-181 ◽  
Author(s):  
M. E. Ricklin ◽  
J. Lorscheider ◽  
A. Waschbisch ◽  
C. Paroz ◽  
S. K. Mehta ◽  
...  
Keyword(s):  
T Cell ◽  
Varicella Zoster Virus ◽  
Cell Response ◽  
T Cell Response ◽  
Varicella Zoster

scholarly journals Functions of the C-Terminal Domain of Varicella-Zoster Virus Glycoprotein E in Viral Replication In Vitro and Skin and T-Cell Tropism In Vivo

2004 ◽  
Vol 78 (22) ◽  
pp. 12406-12415 ◽  
Author(s):  
Jennifer Moffat ◽  
Chengjun Mo ◽  
Jason J. Cheng ◽  
Marvin Sommer ◽  
Leigh Zerboni ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Varicella Zoster Virus ◽  
Point Mutations ◽  
Glycoprotein E ◽  
Varicella Zoster ◽  
Terminal Domain ◽  
C Terminus

ABSTRACT Varicella-zoster virus (VZV) glycoprotein E (gE) is essential for VZV replication. To further analyze the functions of gE in VZV replication, a full deletion and point mutations were made in the 62-amino-acid (aa) C-terminal domain. Targeted mutations were introduced in YAGL (aa 582 to 585), which mediates gE endocytosis, AYRV (aa 568 to 571), which targets gE to the trans-Golgi network (TGN), and SSTT, an “acid cluster” comprising a phosphorylation motif (aa 588 to 601). Substitutions Y582G in YAGL, Y569A in AYRV, and S593A, S595A, T596A, and T598A in SSTT were introduced into the viral genome by using VZV cosmids. These experiments demonstrated a hierarchy in the contributions of these C-terminal motifs to VZV replication and virulence. Deletion of the gE C terminus and mutation of YAGL were lethal for VZV replication in vitro. Mutations of AYRV and SSTT were compatible with recovery of VZV, but the AYRV mutation resulted in rapid virus spread in vitro and the SSTT mutation resulted in higher virus titers than were observed for the parental rOka strain. When the rOka-gE-AYRV and rOka-gE-SSTT mutants were evaluated in skin and T-cell xenografts in SCIDhu mice, interference with TGN targeting was associated with substantial attenuation, especially in skin, whereas the SSTT mutation did not alter VZV infectivity in vivo. These results provide the first information about how targeted mutations of this essential VZV glycoprotein affect viral replication in vitro and VZV virulence in dermal and epidermal cells and T cells within intact tissue microenvironments in vivo.

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