Potent inhibition of drug-resistant HIV protease variants by monoclonal antibodies
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
18329737
DOI
10.1016/j.antiviral.2008.01.009
PII: S0166-3542(08)00045-4
Knihovny.cz E-resources
- MeSH
- Dimerization MeSH
- Genetic Variation * MeSH
- HIV Infections drug therapy virology MeSH
- HIV-1 drug effects enzymology genetics MeSH
- HIV Protease drug effects genetics immunology MeSH
- Immunoglobulin Fragments immunology pharmacology MeSH
- HIV Protease Inhibitors pharmacology MeSH
- Humans MeSH
- Models, Molecular MeSH
- Antibodies, Monoclonal immunology pharmacology MeSH
- Mutation MeSH
- Recombinant Proteins immunology pharmacology MeSH
- Drug Resistance, Viral genetics MeSH
- Antiretroviral Therapy, Highly Active MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- HIV Protease MeSH
- immunoglobulin Fv MeSH Browser
- Immunoglobulin Fragments MeSH
- HIV Protease Inhibitors MeSH
- Antibodies, Monoclonal MeSH
- Recombinant Proteins 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.
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