TY - JOUR
T1 - Enhancement of the HIV-1 inhibitory activity of RANTES by modification of the N-terminal region
T2 - Dissociation from CCR5 activation
AU - Polo, Simona
AU - Nardese, Vanessa
AU - De Santis, Claudio
AU - Arcelloni, Cinzia
AU - Paroni, Rita
AU - Sironi, Francesca
AU - Verani, Alessia
AU - Rizzi, Menico
AU - Bolognesi, Martino
AU - Lusso, Paolo
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
KW - Antiviral activity
KW - Chemokine
KW - Chemokine receptor
KW - HIV-1
KW - Signal transduction
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U2 - 10.1002/1521-4141(200011)30:11<3190::AID-IMMU3190>3.0.CO;2-E
DO - 10.1002/1521-4141(200011)30:11<3190::AID-IMMU3190>3.0.CO;2-E
M3 - Article
C2 - 11093134
AN - SCOPUS:0033746503
VL - 30
SP - 3190
EP - 3198
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 11
ER -