13th International HIV Drug Resistance Workshop


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


IN VITRO RESISTANCE PROFILE OF SMALL MOLECULE HIV ATTACHMENT INHIBITORS

Antiviral Therapy 2004; 9:S9 (abstract 5)

L Fan, NN Zhou, YF Gong, HT Ho, H Fang, B Eggers, J Fang, CB Li, D Langley, J Kadow and PF Lin
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Conn., USA

BACKGROUND: A small molecule inhibitor, BMS- 488043, of HIV-1 attachment has demonstrated clinical antiviral efficacy. A comprehensive knowledge of the in vitro resistance profiles for this class will greatly aid our understanding of potential clinical resistance development and mechanism of action.

METHODS: Phenotypic and genotypic analysis was performed on viral variants selected against several compound analogues using multiple viral strains.

RESULTS: Selected resistance substitutions span the entire envelope, with >9 residues identified at CD4 contact sites. Remarkably, resistant envelopes carrying double contact site substitutions situated distantly in the CD4 binding pocket were also observed, suggesting that compounds interact with critical CD4 binding residues in a pre-CD4 form of gp120. Also, many of the selected substitutions overlap with the epitopes of CD4 binding site antibodies and the residues affecting viral susceptibility to sCD4. Furthermore, three other frequently occurring envelope changes were either at the V1V2 stem or line the CD4 binding pocket. To further elucidate the inhibitor binding location, gp120 variants carrying CD4 binding pocket mutations were generated. Six were shown to be severely defective in compound binding and resistant to compound inhibition of sCD4 binding. Of the emerging substitutions external to the CD4 binding pocket, two common envelope substitutions at M434 and F423 overlapped with the CD4i epitopes. In addition, many selected substitutions are situated at the CCR5 binding sites (in C4 and V3). In fact, interaction of the HIV-1 V3 loopwith a component of the CD4 binding site at the C4 region has been suggested. The V68A change near the N terminus of gp120, and many changes at gp41 may also indirectly influence the shape of compound interaction sites. Together, the data support initial findings that the attachment inhibitors bind to gp120 and function through interference of the gp120/CD4 interactions in the envelopes studied. Results of labelled compound binding and sCD4 competition further support this hypothesis.

CONCLUSIONS: The cumulative data strongly suggest that compound binding affects the residues in the CD4 pocket of gp120. Also, viral susceptibility to HIV-1 attachment inhibitors can be attributed to multiple interactions between various regions of gp120 and gp41, parallel to that observed for viral resistance to neutralization antibodies.

PRESENTING AUTHOR: PF Lin

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2004-06-08
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