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Journal of Virology, July 1999, p. 5577-5585, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Shift of Clinical Human Immunodeficiency Virus Type 1 Isolates from X4 to R5 and Prevention of Emergence of the Syncytium-Inducing Phenotype by Blockade of CXCR4

José A. Esté,1,* Cecilia Cabrera,1 Julià Blanco,1 Arantxa Gutierrez,1 Gary Bridger,2 Geoffrey Henson,2 Bonaventura Clotet,1 Dominique Schols,3 and Erik De Clercq3

Institut de Recerca de la SIDA---Caixa, Retrovirology Laboratory, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain1; AnorMED Inc., Langley, British Columbia V2Y 1N5, Canada2; and Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium3

Received 22 January 1999/Accepted 12 April 1999

The emergence of X4 human immunodeficiency virus type 1 (HIV-1) strains in HIV-1-infected individuals has been associated with CD4+ T-cell depletion, HIV-mediated CD8+ cell apoptosis, and an impaired humoral response. The bicyclam AMD3100, a selective antagonist of CXCR4, selected for the outgrowth of R5 virus after cultivation of mixtures of the laboratory-adapted R5 (BaL) and X4 (NL4-3) HIV strains in the presence of the compound. The addition of AMD3100 to peripheral blood mononuclear cells infected with X4 or R5X4 clinical HIV isolates displaying the syncytium-inducing phenotype resulted in a complete suppression of X4 variants and a concomitant genotypic change in the V2 and V3 loops of the envelope gp120 glycoprotein. The recovered viruses corresponded genotypically and phenotypically to R5 variants in that they could no longer use CXCR4 as coreceptor or induce syncytium formation in MT-2 cells. Furthermore, the phenotype and genotype of a cloned R5 HIV-1 virus converted to those of the R5X4 virus after prolonged culture in lymphoid cells. However, these changes did not occur when the infected cells were cultured in the presence of AMD3100, despite low levels of virus replication. Our findings indicate that selective blockade of the CXCR4 receptor prevents the switch from the less pathogenic R5 HIV to the more pathogenic X4 HIV strains, a process that heralds the onset of AIDS. In this article, we show that it could be possible to redirect the evolution of HIV so as to impede the emergence of X4 strains or to change the phenotype of already-existing X4 isolates to R5.

* Corresponding author. Mailing address: Fundació irsiCaixa, Retrovirology Laboratory, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain. Phone: 34-93-4656374. Fax: 34-93-4653968. E-mail: jaeste{at}ns.hugtip.scs.es.

Journal of Virology, July 1999, p. 5577-5585, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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