title: HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production.
abstract: Many viruses have developed mechanisms to evade the IFN response. Here, HIV-1 was shown to induce a distinct subset of IFN-stimulated genes (ISGs) in monocyte-derived dendritic cells (DCs), without detectable type I or II IFN. These ISGs all contained an IFN regulatory factor 1 (IRF-1) binding site in their promoters, and their expression was shown to be driven by IRF-1, indicating this subset was induced directly by viral infection by IRF-1. IRF-1 and -7 protein expression was enriched in HIV p24 antigen-positive DCs. A HIV deletion mutant with the IRF-1 binding site deleted from the long terminal repeat showed reduced growth kinetics. Early and persistent induction of IRF-1 was coupled with sequential transient up-regulation of its 2 inhibitors, IRF-8, followed by IRF-2, suggesting a mechanism for IFN inhibition. HIV-1 mutants with Vpr deleted induced IFN, showing that Vpr is inhibitory. However, HIV IFN inhibition was mediated by failure of IRF-3 activation rather than by its degradation, as in T cells. In contrast, herpes simplex virus type 2 markedly induced IFNβ and a broader range of ISGs to higher levels, supporting the hypothesis that HIV-1 specifically manipulates the induction of IFN and ISGs to enhance its noncytopathic replication in DCs.
authors.affiliation: Centre for Virus Research, Westmead Millennium Institute, Westmead, Australia.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Harman
authors.forename: Joey
authors.initials: J
authors.lastname: Lai
authors.forename: Stuart
authors.initials: S
authors.lastname: Turville
authors.forename: Shamith
authors.initials: S
authors.lastname: Samarajiwa
authors.forename: Lachlan
authors.initials: L
authors.lastname: Gray
authors.forename: Valerie
authors.initials: V
authors.lastname: Marsden
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Mercier
authors.forename: Sarah
authors.initials: S
authors.lastname: Mercier
authors.forename: Kate
authors.initials: K
authors.lastname: Jones
authors.forename: Najla
authors.initials: N
authors.lastname: Nasr
authors.forename: Arjun
authors.initials: A
authors.lastname: Rustagi
authors.forename: Helen
authors.initials: H
authors.lastname: Cumming
authors.forename: Heather
authors.initials: H
authors.lastname: Donaghy
authors.forename: Johnson
authors.initials: J
authors.lastname: Mak
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.forename: Melissa
authors.initials: M
authors.lastname: Churchill
authors.forename: Paul
authors.initials: P
authors.lastname: Hertzog
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Cunningham
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D015536:Down-Regulation / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007370:Interferon Type I / Q000378:metabolism*; D046228:Microarray Analysis; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I