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Journal of Virology, August 2003, p. 8280-8289, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8280-8289.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Pathogenic Effects of Human Herpesvirus 6 in Human Lymphoid Tissue Ex Vivo

Jean-Charles Grivel,1 Fabio Santoro,2 Silvia Chen,1 Giovanni Fagá,2 Mauro S. Malnati,2 Yoshinori Ito,1 Leonid Margolis,1* and Paolo Lusso2,3*

Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development and NASA/NIH Center for Three Dimensional Tissue Culture, National Institutes of Health, Bethesda, Maryland 20892,1 Unit of Human Virology, Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan,2 Department of Medical Sciences, University of Cagliari, 09123 Cagliari, Italy3

Received 18 March 2003/ Accepted 5 May 2003

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of human immunodeficiency virus disease. However, the lack of suitable experimental models has hampered the elucidation of the mechanisms of HHV-6-mediated immune suppression. Here, we used ex vivo lymphoid tissue to investigate the cellular tropism and pathogenic mechanisms of HHV-6. Viral strains belonging to both HHV-6 subgroups (A and B) were able to productively infect human tonsil tissue fragments in the absence of exogenous stimulation. The majority of viral antigen-expressing cells were CD4+ T lymphocytes expressing a nonnaive phenotype, while CD8+ T cells were efficiently infected only with HHV-6A. Accordingly, HHV-6A infection resulted in the depletion of both CD4+ and CD8+ T cells, whereas in HHV-6B-infected tissue CD4+ T cells were predominantly depleted. The expression of different cellular antigens was dramatically altered in HHV-6-infected tissues: whereas CD4 was upregulated, both CD46, which serves as a cellular receptor for HHV-6, and CD3 were downmodulated. However, CD3 downmodulation was restricted to infected cells, while the loss of CD46 expression was generalized. Moreover, HHV-6 infection markedly enhanced the production of the CC chemokine RANTES, whereas other cytokines and chemokines were only marginally affected. These results provide the first evidence, in a physiologically relevant study model, that HHV-6 can severely affect the physiology of secondary lymphoid organs through direct infection of T lymphocytes and modulation of key membrane receptors and chemokines.

* Corresponding author. Mailing address for Leonid Margolis: Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, NIH, Bldg. 10, Rm. 9D58, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 594-2476. Fax: (301) 480-0857. E-mail: margolis{at}helix.nih.gov. Mailing address for Paolo Lusso: DIBIT-San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. Phone: 39-02-2643282. Fax: 39-02-26434905. E-mail: paolo.lusso{at}hsr.it.

Journal of Virology, August 2003, p. 8280-8289, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8280-8289.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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