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154 Anti-HIV-1 RANTES Derivatives Acting as CCR5 Antagonists Present Full Additivity or Synergy in Combination With Different Entry/Fusion Inhibitors

Secchi, Massimiliano; Vangelista, Luca

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 63
doi: 10.1097/01.qai.0000397339.25729.81

Protein Engineering and Therapeutics Group - Division of Immunology, Transplantation and Infectious Diseases - San Raffaele Scientific Institute, Milan, Italy

Inhibition of HIV-1 entry by CCR5 targeting is a strategy that requires antagonism towards CCR5 to prevent pro-inflammatory conditions. RANTES-based HIV-1 blockers and maraviroc represent the state of the art in this field, and could be envisaged both as systemic drugs and as topical microbicides. In both options, the combination of different drugs represents an advantage in terms of higher efficacy, lower administration dosage and decreased risk of resistant virus strains' emergence. Two anti-HIV-1 CCR5 antagonists have been developed in our laboratory: i) Rmax, the most potent peptide derived from the N-loop/β1-strand region of RANTES; and ii) C1C5 RANTES, a full-length RANTES mutant in which serine residues in positions 1 and 5 were replaced by cysteine. Fully additive or synergistic HIV-1 inhibition is obtained in vitro when RANTES derivatives are tested in combination with maraviroc, cyanovirin-N or T20. Rmax was chemically synthesized while C1C5 RANTES was secreted by engineered lactobacilli, and both have been used after purification. Cell-cell fusion and p24-based assays were performed to determine anti-HIV-1 activity of individual or combined compounds. Results were analyzed using the Calcusyn software to determine inhibitory concentrations (IC) and combination indexes (CI). Rmax and C1C5 RANTES exert their activity against different laboratory and primary HIV-1 R5 strains of clade B and C. Rmax inhibits HIV-1BaL infection with an IC50 similar to that of T20. When tested in combination, full additivity was observed with maraviroc and cyanovirin-N and synergy with a CI50<0.8 was obtained with T20. C1C5 RANTES combination with maraviroc or cyanovirin-N resulted also in a significant synergistic effect on the inhibition of HIV-1BaL infection, with a CI50 of about ∼0.8 for both combinations. No cellular toxicity was observed under all conditions. Our data suggest that RANTES derivatives may be included in systemic or microbicidal anti-HIV-1 cocktails.

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