16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

IN VITRO HIV-1 RESISTANCE SELECTION TO GS-8374, A NOVEL PHOSPHONATE PROTEASE INHIBITOR: COMPARISON WITH LOPINAVIR, ATAZANAVIR AND DARUNAVIR

Antivir Ther. 2007; 12:S18 (abstract no. 16)

C Callebaut, K Stray, L Tsai, L Xu, W Lee and T Cihlar
Gilead Sciences, Foster City, CA, USA

BACKGROUND: GS-8374 is a novel HIV protease inhibitor (PI). Prior analysis has shown that its diethylphosphonate moiety is involved in a novel type of interaction termed solvent anchoring (Cihlar et al., J Mol Biol. 2006 Oct 27;363(3):635-47), which results in a superior in vitro resistance profile against highly PI-resistant HIV-1 variants compared to approved PIs (Callebaut et al, Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 491). Here, we report on the comparison of in vitro resistance selection experiments with GS-8374 and several clinically used PIs.

METHODS: Selections with GS-8374 and other PIs were performed in MT-2 cells infected with HIV-1 IIIB. Resulting viruses were phenotyped using an XTT-based cytopathic assay, and clonal sequencing of the whole Gag–Protease region was performed to identify resistance mutations. Recombinant infectious clones were generated by transferring Gag and/or Protease coding regions from the selected viral strains.

RESULTS: Selections with lopinavir, atazanavir, and darunavir resulted in the emergence of L10F/M46I/ I54V/V82A, I50L/A71V/V77I/N88S and R41T/K70E mutations in Protease, respectively, after 5 months of drug exposure. Viruses selected by lopinavir and atazanavir showed >100-fold resistance to the respective selecting drugs, but no cross-resistance to GS-8374. In contrast, a parallel selection with GS-8374 for 5 months induced only Gag mutations and approximately fivefold reduced susceptibility to GS-8374. Further extension of the selection to 11 months resulted in a Protease mutation R41K together with additional mutations in Gag including changes in gag-pol frameshift region. The final selected isolate exhibited 15-fold reduced susceptibility to GS- 8374, with minimal cross-resistance to other PIs. In accordance with the known polymorphic nature of R41K, recombinant strain containing this mutation in Protease alone was not associated with any changes in susceptibility to either GS-8374 or other tested PIs. Instead, viruses containing mutations in Gag showed susceptibility shift to GS-8374 similar to that observed with the selected virus.

CONCLUSIONS: Direct comparison with several approved PIs suggests a higher genetic barrier for the selection of Protease mutations in the presence of GS-8374. The results indicate a direct role of specific Gag mutations in a selective resistance to GS-8374. Overall, this study further emphasizes the favourable properties of GS-8374 resulting from its unique mode of interaction with HIV protease.

2007-06-12
16

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