HIV-1 Nef induces dendritic cell differentiation: a possible mechanism of uninfected CD4(+) T cell activation.
Human immunodeficiency virus (HIV)-1 Nef protein is an essential modulator of AIDS pathogenesis and we have previously demonstrated that rNef enters uninfected human monocytes and induces T cells bystander activation, up-regulating IL-15 production. Since dendritic cells (DCs) play a central role in HIV-1 primary infection we investigated whether rNef affects DCs phenotypic and functional maturation in order to define its role in the immunopathogenesis of AIDS. We found that rNef up-regulates the expression on immature DCs of surface molecules known to be critical for their APC function. These molecules include CD1a, HLA-DR, CD40, CD83, CXCR4, and to a lower extent CD80 and CD86. On the other hand, rNef down-regulates surface expression of HLA-ABC and mannose receptor. The functional consequence of rNef treatment of immature DCs is a decrease in their endocytic and phagocytic activities and an increase in cytokine (IL-1beta, IL-12, IL-15, TNF-alpha) and chemokine (MIP-1alpha, MIP-1beta, IL-8) production as well as in their stimulatory capacity. These results indicate that rNef induces a coordinate series of phenotypic and functional changes promoting DC differentiation and making them more competent APCs. Indeed, Nef induces CD4(+) T cell bystander activation by a novel mechanism involving DCs, thus promoting virus dissemination.
Quaranta
Maria Giovanna
MG
Laboratory of Immunology, Istituto Superiore di Sanità, Rome, 00161, Italy.
Tritarelli
Elena
E
Giordani
Luciana
L
Viora
Marina
M
D017951:Antigen Presentation; D015703:Antigens, CD / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004705:Endocytosis; D015693:Gene Products, nef / Q000494:pharmacology*; D015497:HIV-1 / Q000472:pathogenicity*; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007700:Kinetics; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D010587:Phagocytosis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D015854:Up-Regulation; D054311:nef Gene Products, Human Immunodeficiency Virus
D015703:Antigens, CD; D018925:Chemokines; D016207:Cytokines; D015693:Gene Products, nef; D006684:HLA-DR Antigens; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D054311:nef Gene Products, Human Immunodeficiency Virus