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Journal of Virology, March 2005, p. 2807-2813, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2807-2813.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Viral Replication-Independent Blockade of Dendritic Cell Maturation and Interleukin-12 Production by Human Herpesvirus 6

Alison P. Smith,1,{dagger} Clara Paolucci,2 Giulia Di Lullo,1 Samuele E. Burastero,2 Fabio Santoro,1 and Paolo Lusso1,3*

Unit of Human Virology,1 Unit of Leukocyte Biology, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan,2 Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy3

Received 5 August 2004/ Accepted 18 October 2004

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive CD4+-T-lymphotropic betaherpesvirus that causes severe human thymocyte depletion in heterochimeric SCID-hu thy/liv mice and has been implicated as a potential cofactor in the progression of AIDS. However, the mechanisms of HHV-6-mediated immunosuppression have not yet been fully elucidated. We investigated the phenotypic and functional alterations induced by HHV-6 on peripheral blood-derived human dendritic cells (DC). The infection of DC with HHV-6 A or B was nonproductive, as revealed by calibrated real-time PCR measuring the accumulation of viral genome equivalents over time. Nevertheless, preexposure to HHV-6 markedly impaired the maturation of DC driven by gamma interferon and lipopolysaccharide, as shown by the reduced surface expression of major histocompatibility complex class I molecules, HLA-DR, CD40, and CD80. Moreover, HHV-6, but not the closely related betaherpesvirus HHV-7, dramatically suppressed the secretion of interleukin-12 (IL-12) p70 by DC, while the production of other cytokines that influence DC maturation, i.e., IL-10 and tumor necrosis factor alpha, was not significantly modified. Likewise, the secretion of the CC chemokines macrophage inflammatory protein 1ß and RANTES was unaltered. Functionally, a pretreatment with HHV-6 impaired the ability of DC to stimulate allogeneic T-cell proliferation. Altogether, these data identify interference with the functional maturation of DC as a potential mechanism of HHV-6-mediated immunosuppression.

* Corresponding author. Mailing address: Unit of Human Virology, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Via Olgettina no. 58, 20132 Milan, Italy. Phone: 39-02-26432821. Fax: 39-02-26432821. E-mail: paolo.lusso{at}hsr.it.

{dagger} Present address: European Institute of Oncology, 20142 Milan, Italy.

Journal of Virology, March 2005, p. 2807-2813, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2807-2813.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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