title: LEDGIN-mediated Inhibition of Integrase-LEDGF/p75 Interaction Reduces Reactivation of Residual Latent HIV.
abstract: Persistence of latent, replication-competent Human Immunodeficiency Virus type 1 (HIV-1) provirus is the main impediment towards a cure for HIV/AIDS (Acquired Immune Deficiency Syndrome). Therefore, different therapeutic strategies to eliminate the viral reservoirs are currently being explored. We here propose a novel strategy to reduce the replicating HIV reservoir during primary HIV infection by means of drug-induced retargeting of HIV integration. A novel class of integration inhibitors, referred to as LEDGINs, inhibit the interaction between HIV integrase and the LEDGF/p75 host cofactor, the main determinant of lentiviral integration site selection. We show for the first time that LEDGF/p75 depletion hampers HIV-1 reactivation in cell culture. Next we demonstrate that LEDGINs relocate and retarget HIV integration resulting in a HIV reservoir that is refractory to reactivation by different latency-reversing agents. Taken together, these results support the potential of integrase inhibitors that modulate integration site targeting to reduce the likeliness of viral rebound.
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium. Electronic address: Lenard.vranckx@med.kuleuven.be.
authors.forename: Lenard S
authors.initials: LS
authors.lastname: Vranckx
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium. Electronic address: Jonas.Demeulemeester@med.kuleuven.be.
authors.forename: Jonas
authors.initials: J
authors.lastname: Demeulemeester
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium. Electronic address: suha.saleh@kuleuven.be.
authors.forename: Suha
authors.initials: S
authors.lastname: Saleh
authors.affiliation: Laboratory of Molecular Virology, Centre for Integrative Biology (CIBIO), University of Trento, Via delle Regole 101, 38123 Trento, Italy. Electronic address: annegret.boll@gmail.com.
authors.forename: Annegret
authors.initials: A
authors.lastname: Boll
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium. Electronic address: Gerlinde.vansant@kuleuven.be.
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Vansant
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium; Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Herestraat 49, 3000 Leuven, Flanders, Belgium. Electronic address: Rik.schrijvers@kuleuven.be.
authors.forename: Rik
authors.initials: R
authors.lastname: Schrijvers
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium. Electronic address: Caroline.weydert@med.kuleuven.be.
authors.forename: Caroline
authors.initials: C
authors.lastname: Weydert
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, 1650 Owens St., 94158 San Francisco, CA, USA. Electronic address: emilie.battivelli@gladstone.ucsf.edu.
authors.forename: Emilie
authors.initials: E
authors.lastname: Battivelli
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, 1650 Owens St., 94158 San Francisco, CA, USA. Electronic address: eric.verdin@gladstone.ucsf.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.affiliation: Laboratory of Molecular Virology, Centre for Integrative Biology (CIBIO), University of Trento, Via delle Regole 101, 38123 Trento, Italy. Electronic address: anna.cereseto@unitn.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Cereseto
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium. Electronic address: Frauke.Christ@med.kuleuven.be.
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium. Electronic address: Rik.Gijsbers@med.kuleuven.be.
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium. Electronic address: Zeger.debyser@med.kuleuven.be.
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology*; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014775:Virus Activation / Q000187:drug effects; D016662:Virus Integration / Q000187:drug effects; D017735:Virus Latency; D014779:Virus Replication / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019428:HIV Integrase Inhibitors; C504649:PSIP1 protein, human; D014157:Transcription Factors; D019427:HIV Integrase
keywords: HIV latency; HIV remission; Integration; LEDGF/p75; LEDGIN