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Prepublished online as a Blood First Edition Paper on June 26, 2003; DOI 10.1182/blood-2002-10-3152.
Submitted October 18, 2002
Accepted June 8, 2003
Selective suppression of IL-12 production by human herpesvirus 6
Alison Smith, Fabio Santoro, Giulia Di Lullo, Lorenzo Dagna, Alessia Verani, and Paolo Lusso*
Unit of Human Virology, San Raffaele Scientific Institute, Milan, Italy; Department of Microbiology, Boston University School of Medicine, Boston, MA, USA
Unit of Human Virology, San Raffaele Scientific Institute, Milan, Italy
Unit of Human Virology, San Raffaele Scientific Institute, Milan, Italy; Department of Medicine, Vita-Salute San Raffaele University, Milan, Italy
Unit of Human Virology, San Raffaele Scientific Institute, Milan, Italy; Department of Medical Sciences, University of Cagliari, Cagliari, Italy
* Corresponding author; email: paolo.lusso{at}hrs.it.
HHV-6 is a potentially immunosuppressive herpesvirus that has been implicated as a potential cofactor in the progression of HIV disease. Exposure of human macrophages to HHV-6 A or B profoundly impaired their ability to produce IL-12 upon stimulation with IFN- and LPS. By contrast, the production of TNF- , RANTES and MIP-1 was not negatively affected. To exclude the involvement of IL-12-suppressive cytokines, such as IL-10 and TNF-, the viral stocks were fractionated by ultracentrifugation. The bulk of the suppressive activity was recovered within the virion-rich pelleted fraction that was virtually devoid of such cytokines. IL-12 suppression was independent of viral replication, and the effect was not abrogated upon ultraviolet-light inactivation of the viral inoculum. The mechanism of HHV-6-mediated IL-12 suppression was investigated by RNase protection assays, which demonstrated unaltered levels of IL-12 p35 mRNA and only a modest reduction in p40 mRNA, which was insufficient to account for the near complete loss of both extra- and intra-cellular IL-12 protein. Moreover, both the IFN- and LPS signaling pathways were intact in HHV-6-treated cells. These data suggest that HHV-6 can dramatically affect the generation of effective cellular immune responses, providing a novel potential mechanism of HHV-6-mediated immunosuppression.
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