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Pathogenesis and Immunity

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

Jean-Charles Grivel, Fabio Santoro, Silvia Chen, Giovanni Fagá, Mauro S. Malnati, Yoshinori Ito, Leonid Margolis, Paolo Lusso
Jean-Charles Grivel
1Laboratory 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
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Fabio Santoro
2Unit of Human Virology, Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan
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Silvia Chen
1Laboratory 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
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Giovanni Fagá
2Unit of Human Virology, Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan
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Mauro S. Malnati
2Unit of Human Virology, Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan
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Yoshinori Ito
1Laboratory 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
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Leonid Margolis
1Laboratory 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
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  • For correspondence: margolis@helix.nih.gov paolo.lusso@hsr.it
Paolo Lusso
2Unit of Human Virology, Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan
3Department of Medical Sciences, University of Cagliari, 09123 Cagliari, Italy
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  • For correspondence: margolis@helix.nih.gov paolo.lusso@hsr.it
DOI: 10.1128/JVI.77.15.8280-8289.2003
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ABSTRACT

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.

  • Copyright © 2003 American Society for Microbiology
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Pathogenic Effects of Human Herpesvirus 6 in Human Lymphoid Tissue Ex Vivo
Jean-Charles Grivel, Fabio Santoro, Silvia Chen, Giovanni Fagá, Mauro S. Malnati, Yoshinori Ito, Leonid Margolis, Paolo Lusso
Journal of Virology Aug 2003, 77 (15) 8280-8289; DOI: 10.1128/JVI.77.15.8280-8289.2003

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Pathogenic Effects of Human Herpesvirus 6 in Human Lymphoid Tissue Ex Vivo
Jean-Charles Grivel, Fabio Santoro, Silvia Chen, Giovanni Fagá, Mauro S. Malnati, Yoshinori Ito, Leonid Margolis, Paolo Lusso
Journal of Virology Aug 2003, 77 (15) 8280-8289; DOI: 10.1128/JVI.77.15.8280-8289.2003
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KEYWORDS

Herpesvirus 6, Human
Palatine Tonsil
Roseolovirus Infections

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