title: LEDGF/p75-independent HIV-1 replication demonstrates a role for HRP-2 and remains sensitive to inhibition by LEDGINs.
abstract: Lens epithelium-derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase (IN) that interacts with IN through its IN binding domain (IBD) and tethers the viral pre-integration complex to the host cell chromatin. Here we report the generation of a human somatic LEDGF/p75 knockout cell line that allows the study of spreading HIV-1 infection in the absence of LEDGF/p75. By homologous recombination the exons encoding the LEDGF/p75 IBD (exons 11 to 14) were knocked out. In the absence of LEDGF/p75 replication of laboratory HIV-1 strains was severely delayed while clinical HIV-1 isolates were replication-defective. The residual replication was predominantly mediated by the Hepatoma-derived growth factor related protein 2 (HRP-2), the only cellular protein besides LEDGF/p75 that contains an IBD. Importantly, the recently described IN-LEDGF/p75 inhibitors (LEDGINs) remained active even in the absence of LEDGF/p75 by blocking the interaction with the IBD of HRP-2. These results further support the potential of LEDGINs as allosteric integrase inhibitors.
authors.affiliation: Division of Molecular Medicine, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Schrijvers
authors.forename: Jan
authors.initials: J
authors.lastname: De Rijck
authors.forename: Jonas
authors.initials: J
authors.lastname: Demeulemeester
authors.forename: Noritaka
authors.initials: N
authors.lastname: Adachi
authors.forename: Sofie
authors.initials: S
authors.lastname: Vets
authors.forename: Keshet
authors.initials: K
authors.lastname: Ronen
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D010421:Pentanoic Acids / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019428:HIV Integrase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C504649:PSIP1 protein, human; D010421:Pentanoic Acids; D013876:Thiophenes; D014157:Transcription Factors; C051610:hepatoma-derived growth factor; C573310:ledgin 7; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1