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Sci Rep. 2018 Jan 30;8(1):1890. doi: 10.1038/s41598-018-20300-9.

Rational CCL5 mutagenesis integration in a lactobacilli platform generates extremely potent HIV-1 blockers.

Author information

1
Protein Engineering and Therapeutics Group, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132, Milan, Italy.
2
INSERM, UMRS-839, Institut du Fer à Moulin, 75005, Paris, France.
3
Protein Engineering and Therapeutics Group, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132, Milan, Italy. vangelista.luca@nu.edu.kz.
4
Department of Biomedical Sciences, School of Medicine, Nazarbayev University, 010000, Astana, Kazakhstan. vangelista.luca@nu.edu.kz.

Abstract

Efforts to improve existing anti-HIV-1 therapies or develop preventatives have identified CCR5 as an important target and CCL5 as an ideal scaffold to sculpt potent HIV-1 entry inhibitors. We created novel human CCL5 variants that exhibit exceptional anti-HIV-1 features using recombinant lactobacilli (exploited for live microbicide development) as a screening platform. Protein design, expression and anti-HIV-1 activity flowed in iterative cycles, with a stepwise integration of successful mutations and refinement of an initial CCL5 mutant battery towards the generation of two ultimate CCL5 derivatives, a CCR5 agonist and a CCR5 antagonist with similar anti-HIV-1 potency. The CCR5 antagonist was tested in human macrophages and against primary R5 HIV-1 strains, exhibiting cross-clade low picomolar IC50 activity. Moreover, its successful combination with several HIV-1 inhibitors provided the ground for conceiving therapeutic and preventative anti-HIV-1 cocktails. Beyond HIV-1 infection, these CCL5 derivatives may now be tested against several inflammation-related pathologies where the CCL5:CCR5 axis plays a relevant role.

PMID:
29382912
PMCID:
PMC5790001
DOI:
10.1038/s41598-018-20300-9
[Indexed for MEDLINE]
Free PMC Article

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