Mutation in Region III of the DNA Polymerase Gene Conferring Foscarnet Resistance in Cytomegalovirus Isolates from 3 Subjects Receiving Prolonged Antiviral Therapy

• Published in: The Journal of infectious diseases Vol. 178; no. 2; pp. 526 - 530
• Main Authors: Chou, Sunwen, Marousek, Gail, Parenti, David M., Gordon, Shelley M., LaVoy, Alison G., Ross, Jennifer G., Miner, Richard C., Drew, W. Lawrence
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 01.08.1998; University of Chicago Press; Oxford University Press
• Subjects: Adult; AIDS-Related Opportunistic Infections - physiopathology; AIDS-Related Opportunistic Infections - virology; AIDS/HIV; Alanine - genetics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - pharmacology; Antivirals; Biological and medical sciences; Codons; Concise Communications; Cytomegalovirus; Cytomegalovirus - drug effects; Cytomegalovirus - enzymology; Cytomegalovirus - genetics; Cytomegalovirus - isolation & purification; Cytomegalovirus Retinitis - physiopathology; Cytomegalovirus Retinitis - virology; DNA; DNA-Directed DNA Polymerase - genetics; Dosage; Drug resistance; Drug Resistance, Microbial - genetics; Foscarnet - pharmacology; Ganciclovir - pharmacology; Genetic mutation; Human immunodeficiency virus 1; Humans; Male; Medical genetics; Medical sciences; Pharmacology. Drug treatments; Phosphotransferases (Alcohol Group Acceptor) - genetics; Point Mutation; Retinitis; Reverse Transcriptase Inhibitors - pharmacology; Valine - genetics; Viral Proteins; Viruses; HIV-1 virus; Betaherpesvirinae; Human cytomegalovirus; Ganciclovir; Multiple resistance; Antiviral; Clinical isolate; Human; Immunopathology; Enzyme; Herpesviridae; Transferases; Foscarnet sodium; Retroviridae; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Nucleotidyltransferases; Chemotherapy; Treatment; Viral disease; Retinitis; Human immunodeficiency virus; Mutation; DNA-directed DNA polymerase
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/515648

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.