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Blood, 15 October 2003, Vol. 102, No. 8, pp. 2877-2884.
Prepublished online as a Blood First Edition Paper on June 26, 2003; DOI 10.1182/blood-2002-10-3152.
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IMMUNOBIOLOGY
Selective suppression of IL-12 production by human herpesvirus 6
Alison Smith,
Fabio Santoro,
Giulia Di Lullo,
Lorenzo Dagna,
Alessia Verani, and
Paolo Lusso
From the Unit of Human Virology, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan, Italy; Department of Microbiology, Boston University School of Medicine, Boston, MA; Department of Medicine, Vita-Salute San Raffaele University, Milan, Italy; and the Department of Medical Sciences, University of Cagliari, Cagliari, Italy.
Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of HIV disease. Exposure of human macrophages to HHV-6A or HHV-6B profoundly impaired their ability to produce interleukin 12 (IL-12) upon stimulation with interferon- (IFN-) and lipopolysaccharide (LPS). By contrast, the production of tumor necrosis factor– (TNF-); regulated on activation, normal T-cell expressed and secreted (RANTES); and macrophage inflammatory protein 1 (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 ultra-centrifugation. 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 extracellular and intracellular IL-12 protein. Moreover, both the IFN- and the 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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