title: Innate Invariant NKT Cell Recognition of HIV-1-Infected Dendritic Cells Is an Early Detection Mechanism Targeted by Viral Immune Evasion.
abstract: Invariant NKT (iNKT) cells are innate-like T cells that respond rapidly with a broad range of effector functions upon recognition of glycolipid Ags presented by CD1d. HIV-1 carries Nef- and Vpu-dependent mechanisms to interfere with CD1d surface expression, indirectly suggesting a role for iNKT cells in control of HIV-1 infection. In this study, we investigated whether iNKT cells can participate in the innate cell-mediated immune response to HIV-1. Infection of dendritic cells (DCs) with Nef- and Vpu-deficient HIV-1 induced upregulation of CD1d in a TLR7-dependent manner. Infection of DCs caused modulation of enzymes in the sphingolipid pathway and enhanced expression of the endogenous glucosylceramide Ag. Importantly, iNKT cells responded specifically to rare DCs productively infected with Nef- and Vpu-defective HIV-1. Transmitted founder viral isolates differed in their CD1d downregulation capacity, suggesting that diverse strains may be differentially successful in inhibiting this pathway. Furthermore, both iNKT cells and DCs expressing CD1d and HIV receptors resided in the female genital mucosa, a site where HIV-1 transmission occurs. Taken together, these findings suggest that innate iNKT cell sensing of HIV-1 infection in DCs is an early immune detection mechanism, which is independent of priming and adaptive recognition of viral Ag, and is actively targeted by Nef- and Vpu-dependent viral immune evasion mechanisms.
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden;
authors.forename: Dominic
authors.identifier: 0000-0003-1407-3414
authors.initials: D
authors.lastname: Paquin-Proulx
authors.affiliation: Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden;
authors.forename: Anna
authors.identifier: 0000-0002-9080-965X
authors.initials: A
authors.lastname: Gibbs
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden;
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Bächle
authors.affiliation: Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; and.
authors.forename: Antonio
authors.identifier: 0000-0002-0674-3329
authors.initials: A
authors.lastname: Checa
authors.affiliation: Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden;
authors.forename: Andrea
authors.identifier: 0000-0002-9929-8964
authors.initials: A
authors.lastname: Introini
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden;
authors.forename: Edwin
authors.identifier: 0000-0003-0505-4967
authors.initials: E
authors.lastname: Leeansyah
authors.affiliation: Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; and.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
authors.affiliation: Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.affiliation: Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden;
authors.forename: Kristina
authors.initials: K
authors.lastname: Broliden
authors.affiliation: Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden;
authors.forename: Annelie
authors.initials: A
authors.lastname: Tjernlund
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden;
authors.forename: Markus
authors.initials: M
authors.lastname: Moll
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden; johan.sandberg@ki.se.
authors.forename: Johan K
authors.identifier: 0000-0002-6275-0750
authors.initials: JK
authors.lastname: Sandberg
mesh_terms: D017951:Antigen Presentation; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005260:Female; D015693:Gene Products, nef / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005963:Glucosylceramides / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D015488:HIV Antigens / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D055611:Natural Killer T-Cells / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology; D054334:Viral Regulatory and Accessory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D055610:Antigens, CD1d; D015693:Gene Products, nef; D005963:Glucosylceramides; D015488:HIV Antigens; D054298:Human Immunodeficiency Virus Proteins; D051199:Toll-Like Receptor 7; D054334:Viral Regulatory and Accessory Proteins; C526877:CD1D protein, human; C495348:TLR7 protein, human; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins