15th International AIDS Conference Bangkok, Thailand - July 11-16, 2004

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1276)

Wild CT, Salzwedel K, Goila-Gaur R, Li F, Castillo A, Kilgore NR, Reddick M, Matallana C, Zoumplis D, Martin DE, Allaway GP, Freed EO
Panacos Pharmaceuticals, Gaithersburg, MD, United States

BACKGROUND: PA-457 is the first in a new class of antiretrovirals that inhibit HIV replication by disrupting virus maturation. PA-457 blocks a late step in Gag processing that results in defective core condensation and the release of non-infectious virus particles. Specifically, PA-457 disrupts the conversion of the capsid precursor, p25 (CA-SP1), to mature CA protein, p24. PA-457's mechanism of action (MOA) is distinct from that of protease inhibitors in that it appears to directly target the Gag precursor protein rather than the viral protease enzyme that is responsible for Gag processing. PA-457-resistant virus isolates were used to map the determinants of the compound's activity.

METHODS: PA-457-resistant virus isolates were selected by continuous culture in the presence of increasing concentrations of compound. Genotyping of resistant virus and preparation of molecular clones with resistance-conferring mutations were carried out using standard methods. PA-457 resistance was characterized using cell-based activity assays and in vitro analysis of Gag processing.

RESULTS: In vitro selection generated PA-457-resistant virus. Genotypic analysis of these isolates revealed two independent patterns of resistance-conferring mutations. Consistent with our MOA studies these mutations map to residues flanking the Gag CA-SP1 cleavage site. An A to V change at either the first or third residues at the N-terminus of SP1 (A1V or A3V) resulted in a resistant phenotype. While these changes resulted in a decrease in sensitivity to PA-457, these viruses remained sensitive to all classes of approved HIV drugs.

CONCLUSIONS: These results support and extend previous observations that PA-457 is a specific inhibitor of CA-SP1 cleavage, with no activity against other Gag processing events. Characterizing the determinants of PA-457 activity is the first step in defining the molecular target for this novel HIV maturation inhibitor.

040711
WeOrA1276

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