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

Massimiliano Secchi, Valentina Grampa, Luca Vangelista

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Article number1890
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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Lactobacillus
Mutagenesis
HIV-1
HIV Fusion Inhibitors
Anti-Infective Agents
Inhibitory Concentration 50
HIV Infections
Macrophages
Pathology
Inflammation
Mutation
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Rational CCL5 mutagenesis integration in a lactobacilli platform generates extremely potent HIV-1 blockers. / Secchi, Massimiliano; Grampa, Valentina; Vangelista, Luca.

In: Scientific Reports, Vol. 8, No. 1, 1890, 01.12.2018.

Research output: Contribution to journalArticle

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