Mutation in region III of the DNA polymerase gene conferring foscarnet resistance in cytomegalovirus isolates from 3 subjects receiving prolonged antiviral therapy.
Three human immunodeficiency virus-infected subjects with progressive cytomegalovirus (CMV) retinitis despite prolonged antiviral therapy had buffy coat CMV isolates that were resistant to both ganciclovir and foscarnet. Genetic analysis of the resistant isolates showed that each contained a well-known ganciclovir resistance mutation in the viral UL97 phosphotransferase sequence, as well as a mutation (Ala to Val at codon 809, V809) in conserved region III of the DNA polymerase (Pol) sequence. A segment of the Pol sequence from one of the clinical isolates was transferred to CMV laboratory strain AD169 by homologous recombination. The recombinant virus containing V809 showed 6.3-fold increased foscarnet resistance and 2.6-fold increased ganciclovir resistance. Occurrence of the V809 mutation in 3 unrelated cases suggests that it is a clinically significant viral genetic marker for foscarnet resistance and decreased susceptibility to ganciclovir.
Chou
S
S
Medical and Research Services, VA Medical Center, Portland, Oregon 97201, USA. chous@ohsu.edu
Marousek
G
G
Parenti
D M
DM
Gordon
S M
SM
LaVoy
A G
AG
Ross
J G
JG
Miner
R C
RC
Drew
W L
WL
D017088:AIDS-Related Opportunistic Infections / Q000503:physiopathology / Q000821:virology*; D000328:Adult; D000409:Alanine / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification; D017726:Cytomegalovirus Retinitis / Q000503:physiopathology / Q000821:virology*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004352:Drug Resistance, Microbial / Q000235:genetics; D017245:Foscarnet / Q000494:pharmacology*; D015774:Ganciclovir / Q000494:pharmacology; D006801:Humans; D008297:Male; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D017354:Point Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014633:Valine / Q000235:genetics; D014764:Viral Proteins
D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; D017245:Foscarnet; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D004259:DNA-Directed DNA Polymerase; D014633:Valine; D000409:Alanine; D015774:Ganciclovir