A deletion mutation in region V of the cytomegalovirus DNA polymerase sequence confers multidrug resistance.
A patient with AIDS and cytomegalovirus (CMV) retinitis received ganciclovir and foscarnet for 20 and 5 months, respectively, with evidence of periodic disease progression. After this therapy, a CMV isolate from the patient was resistant to ganciclovir, foscarnet, and cidofovir. Sequence analysis showed a known ganciclovir resistance mutation in the viral UL97 phosphotransferase (L595F) and a new mutation in conserved region V of the DNA polymerase gene (pol) sequence (codons 981-982 deleted). The pol mutation was transferred to a laboratory CMV strain (Towne) by homologous recombination and selection with either ganciclovir or foscarnet. Recombinant viruses containing this deletion showed a 6-8-fold increased ganciclovir resistance and a 3-5-fold increased resistance to both foscarnet and cidofovir, compared with the wild-type CMV. A single mutation in region V of CMV pol can, therefore, confer multiple drug resistance in a clinical isolate.
Chou
S
S
VA Medical Center P3ID, Portland, OR 97201, USA. chous@ohsu.edu
Miner
R C
RC
Drew
W L
WL
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000188:drug therapy / Q000821:virology; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D017726:Cytomegalovirus Retinitis / Q000150:complications / Q000188:drug therapy / Q000821:virology; D003596:Cytosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D017245:Foscarnet / Q000627:therapeutic use; D015774:Ganciclovir / Q000627:therapeutic use; D017353:Gene Deletion; D006801:Humans; D009154:Mutation; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D010770:Phosphotransferases / Q000235:genetics; D014162:Transfection
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D017245:Foscarnet; D003596:Cytosine; D010770:Phosphotransferases; D004259:DNA-Directed DNA Polymerase; D000077404:Cidofovir; D015774:Ganciclovir