title: Vpu mediates depletion of interferon regulatory factor 3 during HIV infection by a lysosome-dependent mechanism.
abstract: HIV has evolved sophisticated mechanisms to avoid restriction by intracellular innate immune defenses that otherwise serve to control acute viral infection and virus dissemination. Innate defenses are triggered when pattern recognition receptor (PRR) proteins of the host cell engage pathogen-associated molecule patterns (PAMPs) present in viral products. Interferon regulatory factor 3 (IRF3) plays a central role in PRR signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Productive infection of T cells by HIV is dependent upon the targeted proteolysis of IRF3 that occurs through a virus-directed mechanism that results in suppression of innate immune defenses. However, the mechanisms by which HIV controls innate immune signaling and IRF3 function are not defined. Here, we examined the innate immune response induced by HIV strains identified through their differential control of PRR signaling. We identified viruses that, unlike typical circulating HIV strains, lack the ability to degrade IRF3. Our studies show that IRF3 regulation maps specifically to the HIV accessory protein Vpu. We define a molecular interaction between Vpu and IRF3 that redirects IRF3 to the endolysosome for proteolytic degradation, thus allowing HIV to avoid the innate antiviral immune response. Our studies reveal that Vpu is an important IRF3 regulator that supports acute HIV infection through innate immune suppression. These observations define the Vpu-IRF3 interface as a novel target for therapeutic strategies aimed at enhancing the immune response to HIV.
authors.affiliation: University of Washington School of Medicine, Department of Immunology, Seattle, Washington, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Doehle
authors.forename: Kristina
authors.initials: K
authors.lastname: Chang
authors.forename: Arjun
authors.initials: A
authors.lastname: Rustagi
authors.forename: John
authors.initials: J
authors.lastname: McNevin
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D015497:HIV-1 / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D057131:Immune Evasion; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008969:Molecular Sequence Data; D025941:Protein Interaction Mapping; D017385:Sequence Homology; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D054298:Human Immunodeficiency Virus Proteins; D050838:Interferon Regulatory Factor-3; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins