RT Journal Article
SR Electronic
T1 Viral Entry as the Primary Target for the Anti-HIV Activity of Chicoric Acid and Its Tetra-Acetyl Esters
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 641
OP 648
DO 10.1124/mol.58.3.641
VO 58
IS 3
A1 Wim Pluymers
A1 Nouri Neamati
A1 Christophe Pannecouque
A1 Valery Fikkert
A1 Christophe Marchand
A1 Terrence R. Burke, Jr.
A1 Yves Pommier
A1 Dominique Schols
A1 Erik De Clercq
A1 Zeger Debyser
A1 Myriam Witvrouw
YR 2000
UL http://molpharm.aspetjournals.org/content/58/3/641.abstract
AB The antiviral activity of l-chicoric acid against HIV-1 has been attributed previously to the inhibition of HIV-1 integration. This conclusion was based on the inhibition of integrase activity in enzymatic assays and the isolation of a resistant HIV strain with a mutation (G140S) in the integrase gene. Here we show that the primary antiviral target of l-CA and its analogs in cell culture is viral entry. l- and d-chicoric acid (l-CA and d-CA) and their respective tetra-acetyl esters inhibit the replication of HIV-1 (IIIBand NL4.3) and HIV-2 (ROD) in MT-4 cells at a 50% effective concentration (EC50) ranging from 1.7 to 70.6 μM. In a time-of-addition experiment, l-CA, d-CA,l-CATA, and d-CATA were found to interfere with an early event in the viral replication cycle. Moreover,l-CA, d-CA, and their analogs did not inhibit the replication of virus strains that were resistant toward polyanionic and polycationic compounds at subtoxic concentrations. Furthermore, HIV-1 strains resistant to l-CA and d-CA were selected in the presence of l-CA and d-CA, respectively. Mutations were found in the V2, V3, and V4 loop region of the envelope glycoprotein gp120 of the l-CA andd-CA-resistant NL4.3 strains that were not present in the wild-type NL4.3 strain. Recombination of the gp120 gene of the l-CA and d-CA resistant strain in a NL4.3 wild-type molecular clone fully rescued the phenotypic resistance toward l-CA and d-CA. No significant mutations were detected in the integrase gene of the drug-resistant virus strains. Although inhibition of HIV integrase activity byl-CA and its derivatives was confirmed in an oligonucleotide-driven assay, integrase carrying the G140S mutation was inhibited to the same extent as the wild-type integrase.