TY - JOUR
T1 - Selective suppression of IL-12 production by human herpesvirus 6
AU - Smith, Alison
AU - Santoro, Fabio
AU - Di Lullo, Giulia
AU - Dagna, Lorenzo
AU - Verani, Alessla
AU - Lusso, Paolo
PY - 2003/10/15
Y1 - 2003/10/15
N2 - 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-γ (IFN-γ) and lipopolysaccharide (LPS). By contrast, the production of tumor necrosis factor-α (TNF-α); regulated on activation, normal T-cell expressed and secreted (RANTES); and macrophage inflammatory protein 1β (MIP-1β) was not negatively affected. To exclude the involvement of IL-12-suppressive cytokines, such as IL-10 and TNF-α, 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 extracellular and intracellular IL-12 protein. Moreover, both the IFN-γ 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.
AB - 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-γ (IFN-γ) and lipopolysaccharide (LPS). By contrast, the production of tumor necrosis factor-α (TNF-α); regulated on activation, normal T-cell expressed and secreted (RANTES); and macrophage inflammatory protein 1β (MIP-1β) was not negatively affected. To exclude the involvement of IL-12-suppressive cytokines, such as IL-10 and TNF-α, 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 extracellular and intracellular IL-12 protein. Moreover, both the IFN-γ 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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U2 - 10.1182/blood-2002-10-3152
DO - 10.1182/blood-2002-10-3152
M3 - Article
C2 - 12829600
AN - SCOPUS:0141923890
VL - 102
SP - 2877
EP - 2884
JO - Blood
JF - Blood
SN - 0006-4971
IS - 8
ER -