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Targeting spare CC chemokine receptor 5 (CCR5) as a principle to inhibit HIV-1 entry

Jin, Jun
Colin, Philippe
Staropoli, Isabelle
Lima-Fernandes, Evelyne
Ferret, Cécile
Demir, Arzu
Rogée, Sophie
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Published in The Journal of biological chemistry. 2014, vol. 289, no. 27, p. 19042-52
Abstract 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-α-(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 β-arrestin 2·CCR5 complexes, thereby increasing CCR5 down-regulation and HIV-1 inhibition. Together, these results highlight that spare CCR5, which might permit HIV-1 to escape from chemokines, should be targeted for efficient viral blockade.
Keywords Anti-HIV Agents/pharmacologyArrestins/metabolismChemokine CCL5/pharmacologyHEK293 CellsHIV-1/drug effects/physiologyHumansIntracellular Space/drug effects/metabolismReceptors, CCR5/metabolismSignal Transduction/drug effectsVirus Internalization/drug effects
PMID: 24855645
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Research group Hiv (835)
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JIN, Jun et al. Targeting spare CC chemokine receptor 5 (CCR5) as a principle to inhibit HIV-1 entry. In: The Journal of biological chemistry, 2014, vol. 289, n° 27, p. 19042-52. doi: 10.1074/jbc.M114.559831 https://archive-ouverte.unige.ch/unige:73891

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Deposited on : 2015-07-06

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