| Mutations conferring resistance to viral DNA polymerase inhibitors in camelpox virus give different drug-susceptibility profiles in vaccinia virus. | |
| | |
MedLine Citation:
|
PMID: 22532673 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Cidofovir or (S)-HPMPC is one of the three antiviral drugs that might be used for the treatment of orthopoxvirus infections. (S)-HPMPC and its 2,6-diaminopurine counterpart, (S)-HPMPDAP, have been described to select, in vitro, for drug resistance mutations in the viral DNA polymerase (E9L) gene of vaccinia virus (VACV). Here, to extend our knowledge of drug resistance development among orthopoxviruses, we selected, in vitro, camelpox viruses (CMLV) resistant to (S)-HPMPDAP and identified a single amino acid change, T831I, and a double mutation, A314V+A684V, within E9L. The production of recombinant CMLV and VACV carrying these amino acid substitutions (T831I, A314V, or A314V+A684V) demonstrated clearly their involvement in conferring reduced sensitivity to viral DNA polymerase inhibitors, including (S)-HPMPDAP. Both CMLV and VACV harboring the A314V change showed comparable drug-susceptibility profiles to various antivirals and similar impairments in viral growth. In contrast, the single change T831I and the double change A314V+A684V in VACV were responsible for increased levels of drug resistance and for cross-resistance to viral DNA polymerase antivirals that were not observed with their CMLV counterparts. Each amino acid change accounted for an attenuated phenotype of VACV in vivo. Modeling of E9L suggested that the T→I change at position 831 might abolish hydrogen bonds between E9L and the DNA backbone and have a direct impact on the incorporation of the acyclic nucleoside phosphonates. Our findings demonstrate that drug-resistance development in two related orthopoxvirus species may impact drug-susceptibility profiles and viral fitness differently. |
| | |
Authors:
|
Sophie Duraffour; Graciela Andrei; Dimitri Topalis; Marcela Krečmerová; Jean-Marc Crance; Daniel Garin; Robert Snoeck |
Related Documents
:
|
16823583 - Correlation of drug utilisation and morbidity at the municipality level. high use of an... 22449553 - Antimicrobial drug concentrations and sampling techniques in the equine lung. 10996333 - Cardiovascular risk changes after lipid lowering medications: are they predictable? |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-04-24 |
Journal Detail:
|
Title: Journal of virology Volume: 86 ISSN: 1098-5514 ISO Abbreviation: J. Virol. Publication Date: 2012 Jul |
Date Detail:
|
Created Date: 2012-06-08 Completed Date: 2012-08-15 Revised Date: 2013-02-20 |
Medline Journal Info:
|
Nlm Unique ID: 0113724 Medline TA: J Virol Country: United States |
Other Details:
|
Languages: eng Pagination: 7310-25 Citation Subset: IM |
Affiliation:
|
Rega Institute-KU Leuven, Laboratory of Virology and Chemotherapy, Leuven, Belgium. sophie.duraffour@rega.kuleuven.be |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Amino Acid Substitution Animals Antiviral Agents / pharmacology* Cell Line Cytosine / analogs & derivatives, pharmacology DNA-Directed DNA Polymerase / genetics*, metabolism Drug Resistance, Viral* Humans Microbial Sensitivity Tests Molecular Structure Mutant Proteins / genetics, metabolism Mutation, Missense* Organophosphonates / pharmacology Orthopoxvirus / drug effects*, enzymology Recombinant Proteins / genetics, metabolism Selection, Genetic Vaccinia virus / drug effects*, enzymology Viral Plaque Assay |
| Chemical | |
Reg. No./Substance:
|
0/Antiviral Agents; 0/Mutant Proteins; 0/Organophosphonates; 0/Recombinant Proteins; 113852-37-2/cidofovir; 71-30-7/Cytosine; EC 2.7.7.7/DNA-Directed DNA Polymerase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Sequence in the influenza A virus nucleoprotein required for viral polymerase binding and RNA synthe...
Next Document: Replication of herpes simplex virus: egress of progeny virus at specialized cell membrane sites.