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
| Autor: | Thibault Mesplède, Susan P. Colby-Germinario, Mark A. Wainberg, Susan M. Schader, Maureen Oliveira, Daniela Moisi, Peter K. Quashie, Ruxandra-Ilinca Ibanescu |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Genotype Anti-HIV Agents medicine.drug_class viruses In silico HIV Infections Drug resistance HIV Antibodies HIV Envelope Protein gp120 Biology Monoclonal antibody Genes env Antiviral Agents law.invention Piperidines law Cell Line Tumor Microbicide Drug Resistance Viral medicine Humans Pharmacology (medical) Amino Acid Sequence Protein Structure Quaternary Pharmacology Polymorphism Genetic virus diseases Virus Internalization Antibodies Neutralizing Virology Entry inhibitor Infectious Diseases Docking (molecular) Pyrazines HIV-2 HIV-1 Mutagenesis Site-Directed biology.protein Recombinant DNA Antibody Sequence Alignment medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 56:4257-4267 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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 ρM and 7 μM at 50% effective concentrations (EC 50 s). 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. |
| Databáze: | OpenAIRE |
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