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Journal of Virology, November 2002, p. 11425-11433, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11425-11433.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Tropism of Varicella-Zoster Virus for Human Tonsillar CD4⁺ T Lymphocytes That Express Activation, Memory, and Skin Homing Markers

Department of Pediatrics,¹ Department of Microbiology & Immunology,² Department of Pathology, Stanford University, Stanford, California 94305,³ Department of Microbiology, University of Iowa College of Medicine, Iowa City, Iowa 52242⁴

Received 3 June 2002/ Accepted 19 August 2002

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.