Enhancement of the HIV-1 inhibitory activity of RANTES by modification of the N-terminal region: Dissociation from CCR5 activation

Simona Polo, Vanessa Nardese, Claudio De Santis, Cinzia Arcelloni, Rita Paroni, Francesca Sironi, Alessia Verani, Menico Rizzi, Martino Bolognesi, Paolo Lusso

Research output: Contribution to journalArticlepeer-review

Abstract

Although selected chemokines act as natural inhibitors of human immunodeficiency virus (HIV) infection, their inherent proinflammatory activity may limit a therapeutic use. To elucidate whether the antiviral and signaling functions of RANTES can be dissociated, several recombinant analogues mutated at the N terminus were generated and functionally compared with the wild-type (WT) molecule, as well as with three previously described mutants. Substitution of selected residues within the N-terminal region caused a marked loss of antiviral potency. By contrast, two unique analogues (C1.C5-RANTES and L-RANTES) exhibited an increased antiviral activity against different CXCR4-negative HIV-1 isolates grown in primary mononuclear cells or in macrophages. This enhanced HIV-blocking activity was associated with an increased binding affinity for CCR5. Both C1.C5-RANTES and L-RANTES showed a dramatically reduced ability to trigger intracellular calcium mobilization via CCR3 or CCR5, while potently antagonizing the action of the WT chemokine. By contrast, two previously described analogues (RANTES3-68 and AOP-RANTES) maintained a WT ability to trigger CCR5-mediated signaling, while a third one (RANTES9-68) showed a dramatic loss of antiviral activity. These data demonstrate that the antiviral and signaling functions of RANTES can be uncoupled, opening new perspectives for the development of chemokine-based therapeutic approaches for HIV infection.

Original languageEnglish
Pages (from-to)3190-3198
Number of pages9
JournalEuropean Journal of Immunology
Volume30
Issue number11
DOIs
Publication statusPublished - 2000

Keywords

  • Antiviral activity
  • Chemokine
  • Chemokine receptor
  • HIV-1
  • Signal transduction

ASJC Scopus subject areas

  • Immunology

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