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Journal of Virology, May 1999, p. 3544-3550, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Highly Potent RANTES Analogues either Prevent CCR5-Using Human Immunodeficiency Virus Type 1 Infection In Vivo or Rapidly Select for CXCR4-Using Variantsdagger

Donald E. Mosier,1,* Gastón R. Picchio,1 Richard J. Gulizia,1 Rebecca Sabbe,1 Pascal Poignard,1 Laurent Picard,2 Robin E. Offord,3,4 Darren A. Thompson,4 and Jill Wilken4

Department of Immunology-IMM7, The Scripps Research Institute, La Jolla, California 920371; INSERM U.332, Institut Cochin de Génétique Moléculaire, 75014 Paris, France2; Department de Biochimie Médicale, Centre Médical Universitaire, 1211 Geneva 4, Switzerland3; and Gryphon Sciences, South San Francisco, California 940804

Received 28 September 1998/Accepted 20 January 1999

The natural ligands for the CCR5 chemokine receptor, macrophage inflammatory protein 1alpha (MIP-1alpha ), MIP-1beta , and RANTES (regulated on T-cell activation, normal T-cell expressed and secreted), are known to inhibit human immunodeficiency virus (HIV) entry, and N-terminally modified RANTES analogues are more potent than native RANTES in blocking infection. However, potent CCR5 blocking agents may select for HIV-1 variants that use alternative coreceptors at less than fully inhibitory concentrations. In this study, two N-terminal chemical modifications of RANTES produced by total synthesis, aminooxypentane (AOP)-RANTES[2-68] and N-nonanoyl (NNY)-RANTES[2-68], were tested for their ability to prevent HIV-1 infection and to select for coreceptor switch variants in the human peripheral blood lymphocyte-SCID mouse model. Mice were infected with a CCR5-using HIV-1 isolate that requires only one or two amino acid substitutions to use CXCR4 as a coreceptor. Even though it achieved lower circulating concentrations than AOP-RANTES (75 to 96 pM as opposed to 460 pM under our experimental conditions), NNY-RANTES was more effective in preventing HIV-1 infection. However, in a subset of treated mice, these levels of NNY-RANTES rapidly selected viruses with mutations in the V3 loop of envelope that altered coreceptor usage. These results reinforce the case for using agents that block all significant HIV-1 coreceptors for effective therapy.

* Corresponding author. Mailing address: Department of Immunology-IMM7, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (619) 784-9121. Fax: (619) 784-9190. E-mail: dmosier{at}scripps.edu.

dagger Publication no. 11734-IMM from The Scripps Research Institute.

Journal of Virology, May 1999, p. 3544-3550, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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