title: Enhancement of the HIV-1 inhibitory activity of RANTES by modification of the N-terminal region: dissociation from CCR5 activation.
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 (RANTES(3-68) and AOP-RANTES) maintained a WT ability to trigger CCR5-mediated signaling, while a third one (RANTES(9-68)) 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.
authors.affiliation: Unit of Human Virology, DIBIT, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Polo
authors.forename: V
authors.initials: V
authors.lastname: Nardese
authors.forename: C
authors.initials: C
authors.lastname: De Santis
authors.forename: C
authors.initials: C
authors.lastname: Arcelloni
authors.forename: R
authors.initials: R
authors.lastname: Paroni
authors.forename: F
authors.initials: F
authors.lastname: Sironi
authors.forename: A
authors.initials: A
authors.lastname: Verani
authors.forename: M
authors.initials: M
authors.lastname: Rizzi
authors.forename: M
authors.initials: M
authors.lastname: Bolognesi
authors.forename: P
authors.initials: P
authors.lastname: Lusso
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D018946:Chemokine CCL5 / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019713:Receptors, CCR5 / Q000276:immunology; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D018946:Chemokine CCL5; D019713:Receptors, CCR5