Tropism of varicella-zoster virus for human tonsillar CD4(+) T lymphocytes that express activation, memory, and skin homing markers.
Varicella-zoster virus (VZV) is an alphaherpesvirus with the characteristic neurotropism of this group, but VZV also infects T cells productively and downregulates major histocompatibility complex (MHC) class I expression on infected T cells, as shown in the SCID-hu mouse model. T-cell tropism is likely to be critical for the cell-associated viremia associated with primary VZV infection. In these experiments, we found that VZV infects human tonsillar CD4(+) T cells in culture, with 15 to 25% being positive for VZV proteins as detected by polyclonal anti-VZV immunoglobulin G (IgG) staining and monitored by flow cytometry analysis. RNA transcripts for VZV gE, a late gene product, were detected in T-cell populations that expressed VZV surface proteins, but not in the VZV-negative cell fraction. Exposure to phorbol myristate acetate resulted in an increase in VZV-positive T cells, indicating that viral DNA was present within these cells and that VZV gene expression could be induced by T-cell activation. By immune scanning electron microscopy, VZV virions were detected in abundance on the surfaces of infected tonsillar T cells. The predominant CD4(+) T-lymphocyte subpopulations that became infected were activated CD69(+) T cells with the CD45RA(-) memory phenotype. Subsets of CD4(+) T cells that expressed skin homing markers, cutaneous leukocyte antigen, and chemokine receptor 4 were also infected with VZV. By chemotaxis assay, VZV-infected T cells migrated to SDF-1, demonstrating that skin migratory function was intact despite VZV infection. The susceptibility of tonsil T cells to VZV suggests that these cells may be important targets during the initial VZV infection of upper respiratory tract sites. Viral transfer to migrating T cells in the tonsils may facilitate cell-associated viremia, and preferential infection of CD4 T cells that express skin homing markers may enhance VZV transport to cutaneous sites of replication.
Ku
Chia-Chi
CC
Department of Pediatrics, Stanford University, Stanford, California 94305, USA. cck@stanford.edu
Padilla
Jorge A
JA
Grose
Charles
C
Butcher
Eugene C
EC
Arvin
Ann M
AM
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002634:Chemotaxis, Leukocyte; D006562:Herpes Zoster / Q000821:virology*; D014645:Herpesvirus 3, Human / Q000472:pathogenicity*; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D014066:Palatine Tonsil / Q000276:immunology / Q000821:virology*; D016201:Receptors, Lymphocyte Homing; D012867:Skin / Q000276:immunology; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000378:metabolism
D016201:Receptors, Lymphocyte Homing; D014764:Viral Proteins