Viral replication-independent blockade of dendritic cell maturation and interleukin-12 production by human herpesvirus 6.
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 1beta 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.
Smith
Alison P
AP
Unit of Human Virology, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Via Olgettina no. 58, 20132 Milan, Italy.
Paolucci
Clara
C
Di Lullo
Giulia
G
Burastero
Samuele E
SE
Santoro
Fabio
F
Lusso
Paolo
P
D002454:Cell Differentiation; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D015654:Herpesvirus 6, Human / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D016199:Herpesvirus 7, Human / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007108:Immune Tolerance; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D021122:Protein Subunits / Q000096:biosynthesis*; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014779:Virus Replication
D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D021122:Protein Subunits; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma