ANTIVIRAL ACTIVITIES OF NUCLEOSIDES AND NUCLEOTIDES AGAINST WILD-TYPEAND DRUG-RESISTANT STRAINS OF MURINE CYTOMEGALOVIRUS

Resistance of human cytomegalovirus to approved antiviral drugs is bec oming 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, o r -9-(3-hydroxy-2-[phosphonylmethoxy]propyl)cytosine (HPMPC). Plaque r eduction 50% effective concentrations (EC(50)) for the above inhibitor s increased 9-, 7-, and 23-fold, respectively (against the correspondi ng virus), compared to wild-type MCMV. Each virus was then evaluated a gainst other known anti-MCMV agents to determine cross-resistance patt erns. These compounds included 3-hydroxy-phosphonylmethoxypropyl deriv atives of adenine (HPMPA) and guanine (HPMPG), 2-phosphonylmethoxyethy l derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), cyclob utylguanine, acyclovir, and the methylene phosphonate derivatives of a cyclovir (SR3722) and ganciclovir (SR3773). The ganciclovir-resistant MCMV was cross-resistant to foscarnet, HPMPA, HPMPC, HPMPG, SR3722, an d SR3773. The foscarnet-resistant virus was also resistant to acyclovi r, PMEA, PMEDAP, SR3722, and SR3773. The HPMPC-resistant MCMV was cros s-resistant to HPMPA, HPMPG, and SR3773. Changes in susceptibility wer e from 3- to 22-fold relative to the wild-type virus. Virus yield redu ction data correlated with the plaque assay results. Only cyclobutylgu anine was approximately equally active against wild-type and the three drug-resistant MCMVs. The patterns of cross-resistance correlated wit h 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 imm unodeficient mice.