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

Antivir Ther. 2008; 13(Suppl. 3):A32 (abstract no. 30)

F Hamy¹, S Louvel¹, K Salzwedel² and T Klimkait^1,3
1InPheno AG, Basel, Switzerland; ²Panacos Pharmaceuticals, Gaithersburg, MD, USA; ³University of Basel, Basel, Switzerland

BACKGROUND: Maturation inhibitors such as bevirimat (PA-457) impair HIV replication by specifically binding to a region of Gag, thereby inhibiting CA-SP1 cleavage by viral protease and subsequent formation of mature virions. Recent analyses of clinical data suggested that patients who responded well to bevirimat generally had wild-type HIV-1 sequences at Gag residues 369, 370 and 371, while patients who responded poorly generally had polymorphisms at one or more of these residues. These polymorphisms in SP1 are distinct from laboratory-generated resistance mutations located at the CA-SP1 cleavage site. The current study examined in vitro sensitivity to bevirimat of HIV strains bearing various SP1 polymorphisms using the replicative in vitro test, dual-enhancement of Cell Infection to Phenotype Resistance (deCIPhR).

METHODS: The HIV-1 genome from the start of capsid through the end of protease was reverse-amplified from 20 patient-derived HIV-1 isolates bearing either wild-type or polymorphic SP1. Recombinant proviruses were engineered to contain this portion of viral genome within an isogenic pNL4-3 background. The deCIPhR assay was used to quantitatively assess inhibition of viral replication by bevirimat (IC₅₀, IC₉₀ and Hill’s coefficient).

RESULTS: When expressed as resistance factor (ratio of recombinant IC₅₀: wild type IC₅₀) it was possible to distinguish three phenotypic groups with different susceptibility to PA-457: most sensitive (resistance factor <2), intermediate sensitivity (resistance factor between 2 and 10) and least sensitive (resistance factor >10). Sequencing of gag from the 20 proviruses demonstrated that all viruses in the most sensitive group had wild-type sequences at Gag 369/370/371 (QVT), while all viruses in the intermediate and least sensitive groups had one or more polymorphisms at these residues.

CONCLUSIONS: The in vitro replicative system deCIPhR reproducibly assessed in vitro susceptibility to the maturation inhibitor bevirimat using clinical virus samples. The level of in vitro bevirimat sensitivity was closely related to the presence or absence of polymorphisms at Gag residues 369/370/371. This supports the clinical correlation observed between the presence of these polymorphisms and patient response to bevirimat. These results suggest that the deCIPhR assay may have utility in further defining the determinants of bevirimat response.

2008-06-10
30

Copyright © 2008 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.