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Potent inhibition of drug-resistant HIV protease variants by monoclonal antibodies
V. Bartoňová, V. Král, I. Sieglová, J. Brynda, M. Fábry, M. Hořejší, M. Kožíšek, K.G. Šašková, J. Konvalinka, J. Sedláček, P. Řezáčová
Language English Country Netherlands
Grant support
NR8571
MZ0
CEP Register
- MeSH
- Dimerization MeSH
- Financing, Organized MeSH
- Genetic Variation MeSH
- HIV Infections drug therapy virology MeSH
- HIV-1 enzymology genetics drug effects MeSH
- HIV Protease genetics immunology drug effects MeSH
- Immunoglobulin Fragments pharmacology immunology MeSH
- HIV Protease Inhibitors pharmacology MeSH
- Humans MeSH
- Models, Molecular MeSH
- Antibodies, Monoclonal pharmacology immunology MeSH
- Mutation MeSH
- Recombinant Proteins pharmacology immunology MeSH
- Drug Resistance, Viral genetics MeSH
- Antiretroviral Therapy, Highly Active MeSH
- Check Tag
- Humans MeSH
The monoclonal antibodies 1696 and F11.2.32 strongly inhibit the activity of wild-type HIV-1 protease (PR) by binding to epitopes at the enzyme N-terminus (residues 1-6) and flap residues 36-46, respectively. Here we demonstrate that these antibodies are also potent inhibitors of PR variants resistant to active-site inhibitors used as anti-AIDS drugs. Our in vitro experiments revealed that the inhibitory potency of single-chain fragments (scFv) of these antibodies is not significantly affected by the presence of mutations in PR; inhibition constants for drug-resistant protease variants are 5-11 nM and 13-169 nM for scFv1696 and for scFvF11.2.32, respectively. Tethered dimer of HIV-1 PR variant proved to be a model protease variant resistant to dissociative inhibition by 1696, and, strikingly, it also displayed resistance to inhibition by F11.2.32 suggesting that dimer dissociation also plays a role in the inhibitory action of F11.2.32.
References provided by Crossref.org
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