Antiviral activities of nucleosides and nucleotides against wild-type and drug-resistant strains of murine cytomegalovirus.
Resistance of human cytomegalovirus to approved antiviral drugs is becoming a problem of increasing concern. In order to further study drug resistance in a related virus, strains of murine cytomegalovirus (MCMV) have been prepared in vitro by extensive adaptation of the virus to increasingly higher concentrations of either ganciclovir, foscarnet, or (S)-9-(3-hydroxy-2-[phosphonylmethoxy]propyl)cytosine (HPMPC). Plaque reduction 50% effective concentrations (EC50) for the above inhibitors increased 9-, 7-, and 23-fold, respectively (against the corresponding virus), compared to wild-type MCMV. Each virus was then evaluated against other known anti-MCMV agents to determine cross-resistance patterns. These compounds included 3-hydroxy-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and guanine (HPMPG), 2-phosphonylmethoxyethyl derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), cyclobutylguanine, acyclovir, and the methylene phosphonate derivatives of acyclovir (SR3722) and ganciclovir (SR3773). The ganciclovir-resistant MCMV was cross-resistant to foscarnet, HPMPA, HPMPC, HPMPG, SR3722, and SR3773. The foscarnet-resistant virus was also resistant to acyclovir, PMEA, PMEDAP, SR3722, and SR3773. The HPMPC-resistant MCMV was cross-resistant to HPMPA, HPMPG, and SR3773. Changes in susceptibility were from 3- to 22-fold relative to the wild-type virus. Virus yield reduction data correlated with the plaque assay results. Only cyclobutylguanine was approximately equally active against wild-type and the three drug-resistant MCMVs. The patterns of cross-resistance correlated with resistance seen in human cytomegalovirus strains expressing altered DNA polymerase function. The GCV-resistant and HPMPC-resistant viruses were markedly attenuated in their ability to kill severe combined immunodeficient mice.
Smee
D F
DF
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan 84322-5600, USA.
Barnett
B B
BB
Sidwell
R W
RW
Reist
E J
EJ
Holy
A
A
D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D017245:Foscarnet / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006566:Herpesviridae Infections / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D008826:Microbial Sensitivity Tests; D018146:Muromegalovirus / Q000187:drug effects*; D009705:Nucleosides / Q000494:pharmacology*; D009711:Nucleotides / Q000494:pharmacology*; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology
D000998:Antiviral Agents; D009705:Nucleosides; D009711:Nucleotides; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D017245:Foscarnet; D006147:Guanine; D003596:Cytosine; C063638:lobucavir; D000077404:Cidofovir; D015774:Ganciclovir; D000212:Acyclovir