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Title

Highly potent, fully recombinant anti-HIV chemokines: reengineering a low-cost microbicide

Authors
Nedellec, Rebecca
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Published in Proceedings of the National Academy of Sciences. 2008, vol. 105, no. 46, p. 17706-11
Abstract New prevention strategies for use in developing countries are urgently needed to curb the worldwide HIV/AIDS epidemic. The N-terminally modified chemokine PSC-RANTES is a highly potent entry inhibitor against R5-tropic HIV-1 strains, with an inhibitory mechanism involving long-term intracellular sequestration of the HIV coreceptor, CCR5. PSC-RANTES is fully protective when applied topically in a macaque model of vaginal HIV transmission, but it has 2 potential disadvantages related to further development: the requirement for chemical synthesis adds to production costs, and its strong CCR5 agonist activity might induce local inflammation. It would thus be preferable to find a recombinant analogue that retained the high potency of PSC-RANTES but lacked its agonist activity. Using a strategy based on phage display, we set out to discover PSC-RANTES analogs that contain only natural amino acids. We sought molecules that retain the potency and inhibitory mechanism of PSC-RANTES, while trying to reduce CCR5 signaling to as low a level as possible. We identified 3 analogues, all of which exhibit in vitro potency against HIV-1 comparable to that of PSC-RANTES. The first, 6P4-RANTES, resembles PSC-RANTES in that it is a strong agonist that induces prolonged intracellular sequestration of CCR5. The second, 5P12-RANTES, has no detectable G protein-linked signaling activity and does not bring about receptor sequestration. The third, 5P14-RANTES, induces significant levels of CCR5 internalization without detectable G protein-linked signaling activity. These 3 molecules represent promising candidates for further development as topical HIV prevention strategies.
Keywords Anti-Infective Agents/economics/pharmacologyAntiviral Agents/pharmacologyChemokine CCL5/chemistryChemokines/pharmacologyEndocytosis/drug effectsHIV/drug effectsHela CellsHumansLeukocytes, Mononuclear/drug effects/virologyProtein EngineeringReceptors, CCR5/metabolismReceptors, Virus/metabolismRecombinant Proteins/pharmacologyReproducibility of ResultsSignal Transduction/drug effects
Identifiers
PMID: 19004761
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Other version: http://www.pnas.org/content/105/46/17706.full
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Research group HIV (835)
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GAERTNER, Hubert François et al. Highly potent, fully recombinant anti-HIV chemokines: reengineering a low-cost microbicide. In: Proceedings of the National Academy of Sciences, 2008, vol. 105, n° 46, p. 17706-11. https://archive-ouverte.unige.ch/unige:1265

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Deposited on : 2009-03-31

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