[6] IN VITRO ESCAPE OF R5 PRIMARY ISOLATES FROM THE CCR5 ANTAGONIST, UK-427,857, IS DIFFICULT AND INVOLVES CONTINUED USE OF THE CCR5 RECEPTOR

13th International HIV Drug Resistance Workshop

8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain

IN VITRO ESCAPE OF R5 PRIMARY ISOLATES FROM THE CCR5 ANTAGONIST, UK-427,857, IS DIFFICULT AND INVOLVES CONTINUED USE OF THE CCR5 RECEPTOR

Antiviral Therapy 2004; 9:S10

M Westby¹, C Smith-Burchnell¹, J Mori¹, M Lewis¹, R Mansfield¹, J Whitcomb², CJ Petropoulos² and M Perros¹
¹Pfizer Sandwich Laboratories, Kent, UK; and ²ViroLogic, Inc., South San Francisco, Calif., USA

BACKGROUND: The CCR5 antagonist, UK-427,857, is currently in clinical development as a member of a new class of antiretrovirals targeting HIV co-receptor binding. We have performed in vitro serial passage experiments of R5 isolates in the presence of increasing concentrations of the compound in an attempt to understand the pathways that may lead to UK-427,857 resistance.

METHODS: Six R5 HIV-1 primary isolates were serially passaged through mitogen-stimulated PBL in the presence of increasing concentrations of UK-427,857 for up to 20 weeks. Virus cultures that replicated in the presence of high concentrations of UK-427,857 (>1000-fold the parental virus) were generated and stocks were characterized for co-receptor tropism. Env-recombinant pseudotyped viruses were also generated from these stocks and their susceptibility to UK- 427,857 was assessed using the PhenoSense HIV Entry Assay. Individual env clones of resistant variants were sequenced and compared to sequences of parental viruses and drug-free passaged controls.

RESULTS: High-level resistance to UK-427,857 was achieved in 3/6 virus cultures. Two resistant viruses (CC1/85^res and RU570^res) continued to use the CCR5 co-receptor. The third virus (SF162^res) acquired reduced susceptibility to UK-427,857 in both the drug-treated and drug-free passaged control cultures: in each case the resistant variants selected during passaging were able to use CXCR4 as its entry co-receptor. The CC1/85^res and RU570^res viruses exhibited increased sensitivity to a CCR5-specific mAb (2D7), suggesting altered envelope recognition of the external face of the co-receptor. The infectivity of the RU570^res, but not the CC1/85^res, virus was impaired relative to the parental virus. Strain-specific mutations were identified in the gp160 V3 loop regions of CC1/85^res and RU570^res. Resistance to UK-427,857 could not be generated in three R5 virus cultures (92BR017, 92BR018 and 92BR023) during the course of this study.

CONCLUSIONS: Resistance to UK-427,857 was either slow to emerge or did not develop during this study, suggesting there is considerable selective advantage in vitro for continued use of the CCR5 co-receptor in a UK-427,857-sensitive manner. Furthermore, our results indicate that gp160 mutations associated with UK-427,857 resistance may be strain-specific, suggesting that the context of the V3 loop is crucial for CCR5 recognition. These results offer promise for the efficacy and durability of UK-427,857-containing HAART.

PRESENTING AUTHOR: M Westby

Download PDF of this abstract.

2004-06-08
6

Copyright © 2004 - 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.