1. Vpu modulates DNA repair to suppress innate sensing and hyper-integration of HIV-1
- Author
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Lennart Koepke, Daniel Sauter, Konstantin M. J. Sparrer, Meta Volcic, Lisa Wiesmüller, Frank Kirchhoff, Christina M. Stürzel, Nathalie J. Arhel, Thomas G. Hofmann, Thomas Stamminger, Myriam Scherer, Dominik Hotter, University of Ulm (UUlm), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Mainz, Johannes Gutenberg - Universität Mainz (JGU), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Montpellier (UM), and Centre National de la Recherche Scientifique (CNRS)
- Subjects
Gene Expression Regulation, Viral ,Microbiology (medical) ,DNA Repair ,DNA repair ,Virus Integration ,viruses ,Human Immunodeficiency Virus Proteins ,Immunology ,SUMO protein ,HIV Infections ,Biology ,Models, Biological ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Applied Microbiology and Biotechnology ,Microbiology ,03 medical and health sciences ,Immune system ,Complementary DNA ,Genetics ,Humans ,Viral Regulatory and Accessory Proteins ,Nuclear pore ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,030306 microbiology ,Recombinational DNA Repair ,Sumoylation ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,Immunity, Innate ,Long terminal repeat ,Rad52 DNA Repair and Recombination Protein ,3. Good health ,Cell biology ,Bloom syndrome protein ,Host-Pathogen Interactions ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,HIV-1 - Abstract
To avoid innate sensing and immune control, human immunodeficiency virus type 1 (HIV-1) has to prevent the accumulation of viral complementary DNA species. Here, we show that the late HIV-1 accessory protein Vpu hijacks DNA repair mechanisms to promote degradation of nuclear viral cDNA in cells that are already productively infected. Vpu achieves this by interacting with RanBP2-RanGAP1*SUMO1-Ubc9 SUMO E3-ligase complexes at the nuclear pore to reprogramme promyelocytic leukaemia protein nuclear bodies and reduce SUMOylation of Bloom syndrome protein, unleashing end degradation of viral cDNA. Concomitantly, Vpu inhibits RAD52-mediated homologous repair of viral cDNA, preventing the generation of dead-end circular forms of single copies of the long terminal repeat and permitting sustained nucleolytic attack. Our results identify Vpu as a key modulator of the DNA repair machinery. We show that Bloom syndrome protein eliminates nuclear HIV-1 cDNA and thereby suppresses immune sensing and proviral hyper-integration. Therapeutic targeting of DNA repair may facilitate the induction of antiviral immunity and suppress proviral integration replenishing latent HIV reservoirs.
- Published
- 2020