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

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer 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.

Lingua originaleInglese
pagine (da-a)3190-3198
Numero di pagine9
RivistaEuropean Journal of Immunology
Volume30
Numero di pubblicazione11
DOI
Stato di pubblicazionePubblicato - 2000

Fingerprint

Entra nei temi di ricerca di 'Enhancement of the HIV-1 inhibitory activity of RANTES by modification of the N-terminal region: Dissociation from CCR5 activation'. Insieme formano una fingerprint unica.

Cita questo