title: SAMHD1 degradation enhances active suppression of dendritic cell maturation by HIV-1.
abstract: A hallmark of HIV-1 infection is the lack of sterilizing immunity. Dendritic cells (DCs) are crucial in the induction of immunity, and lack of DC activation might underlie the absence of an effective anti-HIV-1 response. We have investigated how HIV-1 infection affects maturation of DCs. Our data show that even though DCs are productively infected by HIV-1, infection does not induce DC maturation. HIV-1 infection actively suppresses DC maturation, as HIV-1 infection inhibited TLR-induced maturation of DCs and thereby decreased the immune stimulatory capacity of DCs. Interfering with SAMHD1 restriction further increased infection of DCs, but did not lead to DC maturation. Notably, higher infection observed with SAMHD1 depletion correlated with a stronger suppression of maturation. Furthermore, blocking reverse transcription rescued TLR-induced maturation. These data strongly indicate that HIV-1 replication does not trigger immune activation in DCs, but that HIV-1 escapes immune surveillance by actively suppressing DC maturation independent of SAMHD1. Elucidation of the mechanism of suppression can lead to promising targets for therapy or vaccine design.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and.
authors.forename: Nina
authors.initials: N
authors.lastname: Hertoghs
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and.
authors.forename: Angelic M G
authors.initials: AM
authors.lastname: van der Aar
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and Laboratory of Viral Immune Pathogenesis, Department of Experimental Immunology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Laurentia C
authors.initials: LC
authors.lastname: Setiawan
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and Laboratory of Viral Immune Pathogenesis, Department of Experimental Immunology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Neeltje A
authors.initials: NA
authors.lastname: Kootstra
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Gringhuis
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and t.b.geijtenbeek@amc.uva.nl.
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D056747:Immunomodulation; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D059748:Proteolysis; D048348:Reverse Transcription; D000076106:SAM Domain and HD Domain-Containing Protein 1; D051193:Toll-Like Receptors / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism; D014779:Virus Replication
chemical_list: D051193:Toll-Like Receptors; C513059:VPX protein, Simian immunodeficiency virus; D054334:Viral Regulatory and Accessory Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins