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Journal of Virology, May 1999, p. 3544-3550, Vol. 73, No. 5
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 1
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 Variants
(MIP-1
), MIP-1
, 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.
Publication no. 11734-IMM from The Scripps Research Institute.
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