XIX International AIDS Conference

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TUPE015 - Poster Exhibition


Activity of the HIV-1 attachment inhibitor BMS-626529 against HIV-1 envelopes resistant to other entry inhibitors

Z. Li1, N. Zhou1, Y. Sun1, N. Ray2, M. Lataillade3, G. Hanna4, M. Krystal1

1Bristol-Myers Squibb, Virology, Wallingford, United States, 2Bristol-Myers Squibb, Clinical Biomarkers, Princeton, United States, 3Bristol-Myers Squibb, Global Clinical Research, Wallingford, United States, 4Bristol-Myers Squibb, Global Clinical Research, Princeton, United States

Background: BMS-626529 is a novel small-molecule attachment inhibitor (AI) that targets HIV-1 gp120 and prevents its binding to CD4. BMS-663068 is a prodrug of BMS-626529, currently in clinical development. BMS-626529 is active against R5- and X4-tropic HIV-1. However its activity against HIV-1 with resistance to other entry inhibitors is unknown. We assessed the activity of BMS-626529 against HIV-1 envelopes resistant to various entry inhibitors and investigated whether resistance to BMS-626529 is associated with a CD4-independent phenotype.
Methods: Two laboratory-derived envelopes with a CD4-independent phenotype (one X4 and one R5-tropic), five envelopes from clinical isolates with pre-existing BMS-626529 resistance and a few site specific mutant BMS-626529 -resistant envelopes were examined either for their potency to BMS-626529 or dependence on CD4 for infectivity. Viruses resistant to other classes of entry inhibitors were also examined for susceptibility to BMS-626529. These include one laboratory and clinical isolate-derived envelope resistant to the investigational anti-CD4 entry inhibitor mAb ibalizumab, a series of R5-tropic maraviroc-resistant envelopes, and five laboratory and clinically derived envelopes resistant to the fusion inhibitor enfuvirtide.
Results: Both CD4-independent laboratory isolates retained sensitivity to BMS-626529 in CD4 negative cells, while HIV-1 envelopes from viruses resistant to BMS-626529 exhibited no evidence of a CD4-independent phenotype. BMS-626529 also exhibited potent inhibitory activity against the ibalizumab and enfuvirtide-resistant envelopes. For the CCR5-tropic maraviroc-resistant envelopes, some remained sensitive to BMS-626529, with others exhibiting decreased susceptibility. However, using sequential clones derived from a patient treated with a CCR5 antagonist, susceptibility to BMS-626529 was shown to be independent from maraviroc resistance.
Conclusions: Clinical use of the prodrug BMS-663068 is unlikely to promote resistance via generation of CD4-independent virus. No cross-resistance between the AI BMS-626529 and other HIV entry inhibitors was observed, which could allow for its use sequentially or concurrently with different classes of entry inhibitors.


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