LEDGIN-mediated Inhibition of Integrase–LEDGF/p75 Interaction Reduces Reactivation of Residual Latent HIV
Lenard S. Vranckx,
Jonas Demeulemeester,
Suha Saleh,
Annegret Boll,
Gerlinde Vansant,
Rik Schrijvers,
Caroline Weydert,
Emilie Battivelli,
Eric Verdin,
Anna Cereseto,
Frauke Christ,
Rik Gijsbers,
Zeger Debyser
Affiliations
Lenard S. Vranckx
Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium
Jonas Demeulemeester
Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium
Suha Saleh
Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium
Annegret Boll
Laboratory of Molecular Virology, Centre for Integrative Biology (CIBIO), University of Trento, Via delle Regole 101, 38123 Trento, Italy
Gerlinde Vansant
Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium
Rik Schrijvers
Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium
Caroline Weydert
Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium
Emilie Battivelli
Gladstone Institute of Virology and Immunology, University of California, 1650 Owens St., 94158 San Francisco, CA, USA
Eric Verdin
Gladstone Institute of Virology and Immunology, University of California, 1650 Owens St., 94158 San Francisco, CA, USA
Anna Cereseto
Laboratory of Molecular Virology, Centre for Integrative Biology (CIBIO), University of Trento, Via delle Regole 101, 38123 Trento, Italy
Frauke Christ
Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium
Rik Gijsbers
Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium
Zeger Debyser
Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium
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.
