期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 27, 页码 19042-19052出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.559831
关键词
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资金
- Agence Nationale de Recherche sur le SIDA (ANRS)
- Fondation ARC
- Fondation pour la Recherche Medicale (FRM)
- SIDACTION
- INSERM
- Institut Pasteur
- Swiss National Science Foundation
- China Scholarship Council
- [ANR-10-LabEx-62-IBEID]
CCR5 binds the chemokines CCL3, CCL4, and CCL5 and is the major coreceptor for HIV-1 entry into target cells. Chemokines are supposed to form a natural barrier against human immunodeficiency virus, type 1 (HIV-1) infection. However, we showed that their antiviral activity is limited by CCR5 adopting low-chemokine affinity conformations at the cell surface. Here, we investigated whether a pool of CCR5 that is not stabilized by chemokines could represent a target for inhibiting HIV infection. We exploited the characteristics of the chemokine analog PSC-RANTES (N-alpha-(n-nonanoyl)- des-Ser(1)-[ L-thioprolyl(2), L-cyclohexylglycyl(3)]RANTES( 4-68)), which displays potent anti-HIV-1 activity. We show that native chemokines fail to prevent high-affinity binding of PSC-RANTES, analog-mediated calcium release (in desensitization assays), and analog-mediated CCR5 internalization. These results indicate that a pool of spare CCR5 may bind PSC-RANTES but not native chemokines. Improved recognition of CCR5 by PSC-RANTES may explain why the analog promotes higher amounts of beta-arrestin2 .CCR5 complexes, thereby increasing CCR5 down-regulation and HIV-1inhibition. Together, these results highlight that spare CCR5, which might permit HIV-1 to escape from chemokines, should be targeted for efficient viral blockade.
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