17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

ROLE OF GAG POLYMORPHISMS IN HIV-1 SENSITIVITY TO THE MATURATION INHIBITOR BEVIRIMAT

Antivir Ther. 2008; 13(Suppl. 3):A31 (abstract no. 29)

K Salzwedel¹, M Reddick¹, C Matallana¹, C Finnegan¹, C Adamson², M Sakalian¹, D Stanley¹, D Martin¹, S McCallister¹, E Freed² and G Allaway^1
1Panacos Pharmaceuticals, Gaithersburg, MD, USA; ²HIV Drug Resistance Program, National Cancer Institute, Frederick, MD, USA

BACKGROUND: The HIV-1 maturation inhibitor bevirimat (PA-457) binds to Gag and specifically inhibits CA-SP1 processing. Previous in vitro resistance selection experiments identified four highly conserved residues proximal to the CA-SP1 cleavage site that are crucial for resistance to bevirimat. However, variable clinical responses to bevirimat have not been associated with these resistance mutations, rather the responses appear to correlate with the polymorphisms located in SP1 downstream of the CA-SP1 cleavage site that are present at baseline in a subset of patients. The current study examines how these polymorphisms affect susceptibility to bevirimat in vitro.

METHODS: HIV-1 bearing polymorphisms in SP1 were generated by point mutation or construction of chimeric Gags containing CA-SP1 regions from bevirimat-treated patients. Gag processing in virions released from bevirimat- treated cells was analyzed by SDS-PAGE. Selected clones, as well as whole viruses isolated from bevirimattreated patients, were also tested for susceptibility to bevirimat in single-cycle infection and virus replication assays using cell lines or primary peripheral blood mononuclear cells.

RESULTS: Viruses containing deletions, substitutions or naturally occurring polymorphisms at Gag positions 369, 370 and 371 in SP1 displayed reduced inhibition of CASP1 cleavage by bevirimat in Gag processing assays. These viruses also displayed reduced susceptibility to bevirimat inhibition in single-cycle infection assays and in virus replication assays in which a high level of input virus inoculum was used. For at least a subset of these viruses, this effect appeared to be multiplicity of infection (MOI)dependent as further titration of the virus inoculum resulted in susceptibility to bevirimat similar to wild type.

CONCLUSIONS: We have identified naturally occurring polymorphisms at Gag positions 369, 370 and 371 in SP1 that reduce the susceptibility of viruses to bevirimat in vitro. These polymorphisms are distinct from previously described resistance mutations in that they have not been observed in resistance selection experiments in vitro and, in contrast to resistance mutations, the effect of the polymorphisms on bevirimat activity appears to be MOI-dependent. The fact that bevirimat is active against the polymorphic viruses under conditions of low viral replication in vitro may help explain why some patients respond to bevirimat despite being infected by virus bearing these polymorphisms.

2008-06-10
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