The Journal of Experimental Medicine
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Published online 27 September 2004 doi:10.1084/jem.20040634
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 7, 917-925
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Varicella-Zoster Virus Transfer to Skin by T Cells and Modulation of Viral Replication by Epidermal Cell Interferon-{alpha}

Chia-Chi Ku1, Leigh Zerboni1, Hideki Ito1, Brad S. Graham2, Mark Wallace2, and Ann M. Arvin1,3

1 Department of Pediatrics, Stanford University, Stanford, CA 94305
3 Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305
2 Infectious Disease Division, Naval Medical Center, San Diego, CA 92134

Address correspondence to Chia-Chi Ku, 300 Pasteur Dr., S356 Stanford University School of Medicine Stanford, CA 94305. Phone: (650) 723-6353; Fax: (650) 725-8040; email: cck{at}stanford.edu

Primary infection with varicella-zoster virus (VZV) causes the characteristic syndrome of varicella, or chickenpox. Experiments in severe combined immunodeficiency mice with human skin grafts (SCIDhu mice) indicate that VZV infection of T cells can mediate transfer of infectious virus to skin. VZV-infected T cells reached epithelial sites of replication within 24 h after entering the circulation. Memory CD4+ T cells were the predominant population recovered from skin in SCIDhu mice given uninfected or infected mononuclear cells, suggesting that immune surveillance by memory T cells may facilitate VZV transfer. The increased susceptibility of memory T cells to VZV infection may further enhance their role in VZV pathogenesis. During VZV skin infection, viral gene products down-regulated interferon-{alpha} to permit focal replication, whereas adjacent epidermal cells mounted a potent interferon-{alpha} response against cell–cell spread. Interleukin-1{alpha}, although activated in VZV-infected cells, did not trigger expression of endothelial adhesion molecules, thereby avoiding early recruitment of inflammatory cells. The prolonged varicella incubation period appears to represent the time required for VZV to overcome antiviral responses of epidermal cells and generate vesicles at the skin surface. Modulation of VZV replication by cutaneous innate immunity may avoid an incapacitating infection of the host that would limit opportunities for VZV transmission.

Key Words: T cell immune surveillance • viral pathogenesis • inflammation • immune evasion • interferon-{alpha}

H. Ito's present address is Department of Dermatology, Jikei University School of Medicine, 3-19-18 Nishishinbashi Minato, Tokyo, Japan.

Abbreviations used in this paper: CLA, cutaneous lymphocyte antigen; HEL, human lung; ICAM, intercellular adhesion molecule; IRF, IFN regulatory factor; SCID, severe combined immunodeficiency; SCIDhu, SCID with human skin grafts; VACM, vascular adhesion molecule; VZV, varicella-zoster virus.


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