In vitro and in vivo inhibition of murine gamma herpesvirus 68 replication by selected antiviral agents.
We have evaluated the susceptibility of the murine gamma herpesvirus 68 (MHV-68) to a variety of antiviral agents. The acyclic nucleoside phosphonate analogs cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine], (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), and adefovir [9-(2-phosphonylmethoxyethyl)adenine] efficiently inhibited the replication of the virus in Vero cells (50% effective concentrations [EC50s], 0.008, 0.06, and 2.2 microg/ml, respectively). Acyclovir, ganciclovir, and brivudin [(E)-5-(2-bromovinyl)-2'-deoxyuridine] had equipotent activities (EC50s, 1.5 to 8 microg/ml), whereas foscarnet and penciclovir were less effective (EC50s, 23 and > or =30 microg/ml, respectively). The novel N-7-substituted nucleoside analog S2242 [7-(1,3-dihydroxy-2-propoxymethyl)purine] inhibited MHV-68 replication by 50% at 0.2 microg/ml. The susceptibilities of MHV-68 and Epstein-Barr virus (EBV) to cidofovir, HPMPA, adefovir, and acyclovir were found to be comparable. However, for penciclovir, ganciclovir, brivudin, and S2242, major differences in the sensitivity of MHV-68 and EBV were observed, suggesting that MHV-68 is not always an optimal surrogate for the study of antiviral strategies for EBV. When evaluated with a model for lethal MHV-68 infections in mice with severe combined immunodeficiency, cidofovir proved to be very efficient in protecting against virus-induced mortality (100% survival at 50 days postinfection), whereas acyclovir, brivudin, and adefovir had little or no effect.
Neyts
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. Johan.Neyts@rega.kuleuven.ac.be
De Clercq
E
E
D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D002522:Chlorocebus aethiops; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D018142:Gammaherpesvirinae / Q000187:drug effects* / Q000502:physiology; D006566:Herpesviridae Infections / Q000188:drug therapy; D051379:Mice; D016513:Mice, SCID; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C020235:brivudine; D003596:Cytosine; D001973:Bromodeoxyuridine; D000077404:Cidofovir; D000212:Acyclovir