| Autor: |
Mosier DE; Department of Immunology-IMM7, The Scripps Research Institute, La Jolla, California 92037, USA. dmosier@scripps.edu, Picchio GR, Gulizia RJ, Sabbe R, Poignard P, Picard L, Offord RE, Thompson DA, Wilken J |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of virology [J Virol] 1999 May; Vol. 73 (5), pp. 3544-50. |
| DOI: |
10.1128/JVI.73.5.3544-3550.1999 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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