HIV-1 Nef Induces Dendritic Cell Differentiation: A Possible Mechanism of Uninfected CD4+ T Cell Activation

• DOI: 10.1006/excr.2002.5497
• Publication Date: 2002-10-06T18:32:46Z
• Authors: Maria Giovanna Qu...; Elena Tritarelli; Luciana Giordani; Marina Viora
• Keywords: CD4-Positive T-Lymphocytes; 0301 basic medicine; Antigen Presentation; Cell Differentiation; Receptors, Cell Surface; Dendritic Cells; HLA-DR Antigens; Lymphocyte Activation; Endocytosis; Gene Products, nef; 3. Good health; Kinetics; 03 medical and health sciences; Mannose-Binding Lectins; Phagocytosis; Antigens, CD; HIV-1; Cytokines; Humans; Lectins, C-Type; Chemokines; Cells, Cultured; Mannose Receptor

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.