title: Interferon-α Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms.
abstract: HIV-1 is transmitted primarily across mucosal surfaces and rapidly spreads within the intestinal mucosa during acute infection. The type I interferons (IFNs) likely serve as a first line of defense, but the relative expression and antiviral properties of the 12 IFNα subtypes against HIV-1 infection of mucosal tissues remain unknown. Here, we evaluated the expression of all IFNα subtypes in HIV-1-exposed plasmacytoid dendritic cells by next-generation sequencing. We then determined the relative antiviral potency of each IFNα subtype ex vivo using the human intestinal Lamina Propria Aggregate Culture model. IFNα subtype transcripts from the centromeric half of the IFNA gene complex were highly expressed in pDCs following HIV-1 exposure. There was an inverse relationship between IFNA subtype expression and potency. IFNα8, IFNα6 and IFNα14 were the most potent in restricting HIV-1 infection. IFNα2, the clinically-approved subtype, and IFNα1 were both highly expressed but exhibited relatively weak antiviral activity. The relative potencies correlated with binding affinity to the type I IFN receptor and the induction levels of HIV-1 restriction factors Mx2 and Tetherin/BST-2 but not APOBEC3G, F and D. However, despite the lack of APOBEC3 transcriptional induction, the higher relative potency of IFNα8 and IFNα14 correlated with stronger inhibition of virion infectivity, which is linked to deaminase-independent APOBEC3 restriction activity. By contrast, both potent (IFNα8) and weak (IFNα1) subtypes significantly induced HIV-1 GG-to-AG hypermutation. The results unravel non-redundant functions of the IFNα subtypes against HIV-1 infection, with strong implications for HIV-1 mucosal immunity, viral evolution and IFNα-based functional cure strategies.
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America; Department of Immunology and Microbiology, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Harper
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Kejun
authors.initials: K
authors.lastname: Guo
authors.affiliation: Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gibbert
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Dillon
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Barrett
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Martin D
authors.initials: MD
authors.lastname: McCarter
authors.affiliation: Rocky Mountain Laboratories, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America.
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Hasenkrug
authors.affiliation: Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America; Department of Immunology and Microbiology, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Cara C
authors.initials: CC
authors.lastname: Wilson
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America; Department of Immunology and Microbiology, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Mario L
authors.initials: ML
authors.lastname: Santiago
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology* / Q000494:pharmacology; D014771:Virion / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha