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Session 58 Poster Session Entry Inhibitors Session Time: 4:30-6:30 pm Room 4E-F

396-T. HIV-1 Mutants Less Susceptible to SCH-D, a Novel Small-Molecule Antagonist of CCR5 Z. Chen*1, B. Hu1, W. Huang2, T. He1, Y. Huang1, J. Strizki3, S. Xu3, L. Wojcik3, J. M. Whitcomb2, L. Zhang1, C. J. Petropoulos2, B. Baroudy3, and D. Ho1 1Aaron Diamond AIDS Res. Ctr., Rockefeller Univ., New York, NY; 2ViroLogic, Inc., South San Francisco, CA; and 3Schering-Plough Res. Inst., Kenilworth, NJ Background: SCH-D is a small-molecule antagonist of CCR5 that is in preclinical development. The antiviral potency of SCH-D is superior to that of SCH-C, which is in clinical trials. The goal of this study is to understand the evolution of an R5-tropic HIV-1 under the selective pressure of SCH-D in vitro. Methods: The potency of anti-CCR5 compounds was evaluated by measuring the IC50 values using a PBMC culture assay. To generate SCH-D-resistant viruses, HIV-1JR-FL was serially passaged in human PBMC under drug selection. Viral env genes from multiple passages were subjected to sequence analysis, and to functional evaluation using a luciferase-reporter virus assay of ViroLogic, Inc. Results: The mean IC50 of SCH-D was in the range of 0.1-3 nM for a panel of R5-tropic, primary HIV-1 isolates, whereas that of SCH-C was 1-30 nM in parallel experiments. This potency appeared to be independent of viral genotypes, as HIV-1 strains of subtypes A, B, C, and E, as well as group O, gave similar results. After > 30 passages of HIV-1JR-FL in the presence of drug selection, the virus became about 15 times less susceptible than the parental strain in the PBMC assay. These results were further confirmed by analyzing the function of viral envelopes derived from serial passages using the luciferase-reporter virus assay. The less susceptible phenotype became most prominent by passage 24 and all subsequent viruses were clearly cross-resistant to SCH-C and 2 other anti-CCR5 compounds from Schering-Plough, suggesting that these compounds have overlapping targets on CCR5. Interestingly, all less susceptible viral envelopes tested remained R5-tropic; there was no emergence of X4-tropic viruses. Sequence analysis of serial envelopes has revealed 23 amino-acid differences between passage-24 and parental viruses, including 13 scattered in gp120 and 10 in gp41. A careful mutagenesis study, however, is needed to address the biological relevance of the individual changes. Conclusions: SCH-D is a potent antiretroviral compound with broad activity against a panel of R5-tropic viruses of various genotypes. Virus less susceptible to SCH-D, however, emerges under selective pressure of the drug in vitro. This phenotype is conferred by changes in the env gene, although the critical mutations remain to be defined. These findings will provide guidance for the clinical evaluation of SCH-D.

©2002 9th Conference on Retroviruses and Opportunistic Infections