HIV gp120 H375 is unique to HIV-1 subtype CRF01-AE and confers strong resistance to the entry inhibitor BMS-599793, a candidate microbicide drug

Susan M. Schader, Susan P. Colby-Germinario, Peter K. Quashie, Maureen Oliveira, Ruxandra Ilinca Ibanescu, Daniela Moisi, Thibault Mespléde, Mark A. Wainberg

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

BMS-599793 is a small molecule entry inhibitor that binds to human immunodeficiency virus type 1 (HIV-1) gp120, resulting in the inhibition of CD4-dependent entry into cells. Since BMS-599793 is currently considered a candidate microbicide drug, we evaluated its efficacy against a number of primary patient HIV isolates from different subtypes and circulating recombinant forms (CRFs) and showed that activity varied between ∼3 ρMand 7 μMat 50% effective concentrations (EC50s). Interestingly, CRF01-AE HIV-1 isolates consistently demonstrated natural resistance against this compound. Genotypic analysis of > 1,600 sequences (Los Alamos HIV sequence database) indicated that a single amino acid polymorphism in Env, H375, may account for the observed BMS-599793 resistance in CRF01-AE HIV-1. Results of site-directed mutagenesis experiments confirmed this hypothesis, and in silico drug docking simulations identified a drug resistance mechanism at the molecular level. In addition, CRF01-AE viruses were shown to be resistant to multiple broadly neutralizing monoclonal antibodies. Thus, our results not only provide insight into how Env polymorphisms may contribute to entry inhibitor resistance but also may help to elucidate how HIV can evade some broadly neutralizing antibodies. Furthermore, the high frequency of H375 in CRF01-AE HIV-1, and its apparent nonoccurrence in other subtypes, could serve as a means for rapid identification of CRF01-AE infections.

Original languageEnglish
Pages (from-to)4257-4267
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume56
Issue number8
DOIs
Publication statusPublished - Aug 2012
Externally publishedYes

Fingerprint

Dive into the research topics of 'HIV gp120 H375 is unique to HIV-1 subtype CRF01-AE and confers strong resistance to the entry inhibitor BMS-599793, a candidate microbicide drug'. Together they form a unique fingerprint.

Cite this