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First published on July 9, 2004; DOI: 10.1124/mol.104.001735

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Received for publication April 23, 2004.
Revised June 14, 2004.
Accepted for publication July 8, 2004.

Nuclear import of HIV-1 integrase is inhibited in vitro by styrylquinoline derivatives

Aurelie Mousnier 1, Herve Leh 2, Jean-Francois Mouscadet 3, Catherine Dargemont 1*

1 Institut Jacques Monod, UMR7592, CNRS, Universites Paris 6 et 7 2 Bioalliance Pharma 3 Ecole Normale Superieure de Cachan

* Address correspondence to: E-mail: dargemont{at}ijm.jussieu.fr

Abstract

Nuclear import of HIV-1 preintegration complexes (PICs) allows the virus to infect non-dividing 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 non-toxic concentrations and to inhibit IN 3'-processing activity in vitro by competiting with the DNA substrate binding. However, several lines of evidence suggested that SQs could have a post-entry, pre-integrative antiviral effect in infected cells. In order 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 to 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.


Key words: Structure/function/mechanism, Antiviral drugs


This article has been cited by other articles:


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S. Rabaaoui, F. Zouhiri, A. Lancon, H. Leh, J. d'Angelo, and E. Wattel
Inhibitors of Strand Transfer That Prevent Integration and Inhibit Human T-Cell Leukemia Virus Type 1 Early Replication
Antimicrob. Agents Chemother., October 1, 2008; 52(10): 3532 - 3541.
[Abstract] [Full Text] [PDF]


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