title: Overactivation of plasmacytoid dendritic cells inhibits antiviral T-cell responses: a model for HIV immunopathogenesis.
abstract: A delicate balance between immunostimulatory and immunosuppressive signals mediated by dendritic cells (DCs) and other antigen-presenting cells (APCs) regulates the strength and efficacy of antiviral T-cell responses. HIV is a potent activator of plasmacytoid DCs (pDCs), and chronic pDC activation by HIV promotes the pathogenesis of AIDS. Cholesterol is pivotal in maintaining HIV envelope integrity and allowing HIV-cell interaction. By depleting envelope-associated cholesterol to different degrees, we generated virions with reduced ability to activate pDCs. We found that APC activation was dissociated from the induction of type I IFN-α/β and indoleamine-2,3-dioxygenase (IDO)-mediated immunosuppression in vitro. Extensive cholesterol withdrawal, resulting in partial protein and RNA loss from the virions, rendered HIV a more powerful recall immunogen for stimulating memory CD8 T-cell responses in HIV-exposed, uninfected individuals. These enhanced responses were dependent on the inability of cholesterol-depleted HIV to induce IFN-α/β.
authors.affiliation: Immunology Section, Chelsea and Westminster Hospital, Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Imperial College, London, United Kingdom. a.boasso@imperial.ac.uk
authors.forename: Adriano
authors.initials: A
authors.lastname: Boasso
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Royle
authors.forename: Spyridon
authors.initials: S
authors.lastname: Doumazos
authors.forename: Veronica N
authors.initials: VN
authors.lastname: Aquino
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.forename: Luca
authors.initials: L
authors.lastname: Piacentini
authors.forename: Barbara
authors.initials: B
authors.lastname: Tavano
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzotta
authors.forename: Sergio
authors.initials: S
authors.lastname: Lo Caputo
authors.forename: Gene M
authors.initials: GM
authors.lastname: Shearer
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.forename: David R
authors.initials: DR
authors.lastname: Graham
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002784:Cholesterol / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015658:HIV Infections / Q000209:etiology* / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity*; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis; D018448:Models, Immunological; D009000:Monocytes / Q000276:immunology; D012367:RNA, Viral / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*
chemical_list: D018122:B7-1 Antigen; D054298:Human Immunodeficiency Virus Proteins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007370:Interferon Type I; D012367:RNA, Viral; D002784:Cholesterol