title: Nuclear import of HIV-1 integrase is inhibited in vitro by styrylquinoline derivatives.
abstract: Nuclear import of HIV-1 preintegration complexes (PICs) allows the virus to infect nondividing cells. Integrase (IN), the PIC-associated viral enzyme responsible for the integration of the viral genome into the host cell DNA, displays karyophilic properties and has been proposed to participate to the nuclear import of the PIC. Styrylquinolines (SQs) have been shown to block viral replication at nontoxic concentrations and to inhibit IN 3'-processing activity in vitro by competing with the DNA substrate binding. However, several lines of evidence suggested that SQs could have a postentry, preintegrative antiviral effect in infected cells. To gain new insights on the mechanism of their antiviral activity, SQs were assayed for their ability to affect nuclear import of HIV-1 IN and compared with the effect of a specific strand transfer inhibitor. Using an in vitro transport assay, we have previously shown that IN import is a saturable mechanism, thus showing that a limiting cellular factor is involved in this process. We now demonstrate that SQs specifically and efficiently inhibit in vitro nuclear import of IN without affecting other import pathways, whereas a specific strand transfer inhibitor does not affect IN import. These data suggest that SQs not only inhibit IN-DNA interaction but would also inhibit the interaction between IN and the cellular factor required for its nuclear import.
authors.affiliation: Institut Jacques Monod, Unité Mixte de Recherche R 7592 Centre National de la Recherche Scientifique, Universités Paris 6 et 7, 2 Place Jussieu, Tour 43, 75251 Paris Cedex 05, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Mousnier
authors.forename: Hervé
authors.initials: H
authors.lastname: Leh
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mouscadet
authors.forename: Catherine
authors.initials: C
authors.lastname: Dargemont
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects* / Q000502:physiology; D001692:Biological Transport; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D011804:Quinolines / Q000494:pharmacology*
chemical_list: D019428:HIV Integrase Inhibitors; D011804:Quinolines; C481600:styrylquinoline; D004247:DNA; D019427:HIV Integrase