Selective suppression of IL-12 production by human herpesvirus 6.
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-gamma (IFN-gamma) and lipopolysaccharide (LPS). By contrast, the production of tumor necrosis factor-alpha (TNF-alpha); regulated on activation, normal T-cell expressed and secreted (RANTES); and macrophage inflammatory protein 1 beta (MIP-1 beta) was not negatively affected. To exclude the involvement of IL-12-suppressive cytokines, such as IL-10 and TNF-alpha, 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-gamma 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.
Smith
Alison
A
Unit of Human Virology, Department of Biological and Technological Research, San Raffaele Scientific Institute, Via Olgettina n 58, Milan 20132, Italy.
Santoro
Fabio
F
Di Lullo
Giulia
G
Dagna
Lorenzo
L
Verani
Alessia
A
Lusso
Paolo
P
D015703:Antigens, CD / Q000096:biosynthesis; D015153:Blotting, Western; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006678:HIV / Q000378:metabolism; D015654:Herpesvirus 6, Human / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014461:Ultracentrifugation; D014466:Ultraviolet Rays
D015703:Antigens, CD; C497857:CD46 protein, human; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D012260:Ribonucleases