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

doi:10.1016/j.ebiom.2016.04.039

LEDGIN-mediated Inhibition of Integrase-LEDGF/p75 Interaction Reduces Reactivation of Residual Latent HIV

EBioMedicine. 2016 Jun:8:248-264. doi: 10.1016/j.ebiom.2016.04.039. Epub 2016 May 13.

Authors

Affiliations

¹ 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: [email protected].
² 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: [email protected].
³ 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: [email protected].
⁴ Laboratory of Molecular Virology, Centre for Integrative Biology (CIBIO), University of Trento, Via delle Regole 101, 38123 Trento, Italy. Electronic address: [email protected].
⁵ 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: [email protected].
⁶ 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: [email protected].
⁷ 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: [email protected].
⁸ Gladstone Institute of Virology and Immunology, University of California, 1650 Owens St., 94158 San Francisco, CA, USA. Electronic address: [email protected].
⁹ Gladstone Institute of Virology and Immunology, University of California, 1650 Owens St., 94158 San Francisco, CA, USA. Electronic address: [email protected].
¹⁰ Laboratory of Molecular Virology, Centre for Integrative Biology (CIBIO), University of Trento, Via delle Regole 101, 38123 Trento, Italy. Electronic address: [email protected].
¹¹ 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: [email protected].
¹² 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: [email protected].
¹³ 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: [email protected].

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.

Keywords: HIV latency; HIV remission; Integration; LEDGF/p75; LEDGIN.

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / virology
Cell Line
Cell Nucleus / metabolism
HIV Infections / metabolism*
HIV Infections / virology*
HIV Integrase / metabolism*
HIV Integrase Inhibitors / pharmacology*
HIV-1 / drug effects*
HIV-1 / physiology*
Humans
Protein Binding / drug effects
Protein Transport
Transcription Factors / metabolism*
Transcription, Genetic
Virus Activation / drug effects
Virus Integration / drug effects
Virus Latency*
Virus Replication / drug effects

Substances

Adaptor Proteins, Signal Transducing
HIV Integrase Inhibitors
PSIP1 protein, human
Transcription Factors
HIV Integrase

Grants and funding

P30 AI027763/AI/NIAID NIH HHS/United States