title: HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor.
abstract: The binding of integrase (IN) to lens epithelium-derived growth factor (LEDGF)/p75 in large part determines the efficiency and specificity of HIV-1 integration. However, a significant residual preference for integration into active genes persists in Psip1 (the gene that encodes for LEDGF/p75) knockout (KO) cells. One other cellular protein, HRP2, harbors both the PWWP and IN-binding domains that are important for LEDGF/p75 co-factor function. To assess the role of HRP2 in HIV-1 integration, cells generated from Hdgfrp2 (the gene that encodes for HRP2) and Psip1/Hdgfrp2 KO mice were infected alongside matched control cells. HRP2 depleted cells supported normal infection, while disruption of Hdgfrp2 in Psip1 KO cells yielded additional defects in the efficiency and specificity of integration. These deficits were largely restored by ectopic expression of either LEDGF/p75 or HRP2. The double-KO cells nevertheless supported residual integration into genes, indicating that IN and/or other host factors contribute to integration specificity in the absence of LEDGF/p75 and HRP2. Psip1 KO significantly increased the potency of an allosteric inhibitor that binds the LEDGF/p75 binding site on IN, a result that was not significantly altered by Hdgfrp2 disruption. These findings help to rule out the host factor-IN interactions as the primary antiviral targets of LEDGF/p75-binding site IN inhibitors.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Kellie A
authors.initials: KA
authors.lastname: Jurado
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wu
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Shun
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Ferris
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Smith
authors.forename: Pratiq A
authors.initials: PA
authors.lastname: Patel
authors.forename: James R
authors.initials: JR
authors.lastname: Fuchs
authors.forename: Peter
authors.initials: P
authors.lastname: Cherepanov
authors.forename: Mamuka
authors.initials: M
authors.lastname: Kvaratskhelia
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Alan
authors.initials: A
authors.lastname: Engelman
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011804:Quinolines / Q000494:pharmacology; D016662:Virus Integration
chemical_list: D000085:Acetates; C578374:BI-D compound; D019428:HIV Integrase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D011804:Quinolines; C051610:hepatoma-derived growth factor; C119380:lens epithelium-derived growth factor