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Journal of Virology, June 2003, p. 6637-6644, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6637-6644.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Entry Inhibitors Selected on Living Cells from a Library of Phage Chemokines

Oliver Hartley,1 Karim Dorgham,2 Danielle Perez-Bercoff,3 Fabrice Cerini,1 Anouk Heimann,1 Hubert Gaertner,1 Robin E. Offord,1 Gianfranco Pancino,3 Patrice Debré,2 and Guy Gorochov2*

Immunologie A, CERVI, INSERM U543, Hôpital Pitié-Salpêtrière,2 Unité de Biologie des Rétrovirus, Institut Pasteur, Paris, France,3 Département de Biochimie Médicale, Centre Médical Universitaire, Geneva, Switzerland1

Received 26 November 2002/ Accepted 19 March 2003

The chemokine receptors CCR5 and CXCR4 are promising non-virus-encoded targets for human immunodeficiency virus (HIV) therapy. We describe a selection procedure to isolate mutant forms of RANTES (CCL5) with antiviral activity considerably in excess of that of the native chemokine. The phage-displayed library of randomly mutated and N-terminally extended variants was screened by using live CCR5-expressing cells, and two of the selected mutants, P1 and P2, were further characterized. Both were significantly more potent HIV inhibitors than RANTES, with P2 being the most active (50% inhibitory concentration of 600 pM in a viral coat-mediated cell fusion assay, complete protection of target cells against primary HIV type 1 strains at a concentration of 10 nM). P2 resembles AOP-RANTES in that it is a superagonist of CCR5 and potently induces receptor sequestration. P1, while less potent than P2, has the advantage of significantly reduced signaling activity via CCR5 (30% of that of RANTES). Additionally, both P1 and P2 exhibit not only significantly increased affinity for CCR5 but also enhanced receptor selectivity, retaining only trace levels of signaling activity via CCR1 and CCR3. The phage chemokine approach that was successfully applied here could be adapted to other chemokine-chemokine receptor systems and used to further improve the first-generation mutants reported in this paper.

* Corresponding author. Mailing address: Unité INSERM 543, CERVI, Hôpital Pitié-Salpêtrière, 83 Bvd. de L'Hôpital, 75013, Paris, France. Phone: 33 1 42 17 75 07. Fax: 33 1 42 17 74 90. E-mail: guy.gorochov{at}psl.ap-hop-paris.fr.

Journal of Virology, June 2003, p. 6637-6644, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6637-6644.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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