Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine for the treatment of lethal vaccinia virus infections in severe combined immune deficiency (SCID) mice.
Severe combined immune deficient (SCID) mice inoculated intravenously with vaccinia virus (VV) became sick within 6-8 days and died 10-12 days after infection. Tail lesions developed and the number depended on the virus inoculum. Age-matched immunocompetent NMRI mice similarly infected also developed tail lesions but did not become sick. When the infected SCID mice were treated with the acyclic nucleoside phosphonate HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine], either for 5 consecutive days starting on the day of infection or for 5 consecutive days starting on day 2, 4, or 6 post infection, or as a single dose at 7 days or 1 day before infection, VV-associated death was significantly delayed. VV-infected SCID mice that received two doses of 20 mg/kg of HPMPC every week survived the infection for about 130 days. The period during which the mice remained disease-free following HPMPC treatment correlated with the absence of detectable virus in their organs. The VV/SCID mouse model employed here may be useful for determining whether (attenuated) recombinant VV (carrying HIV genes) may have detrimental effects in the immunodeficient host. HPMPC may be considered as a drug candidate for the treatment and prophylaxis of such complications.
Neyts
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
De Clercq
E
E
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000382:microbiology; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000382:microbiology; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology; D051379:Mice; D016513:Mice, SCID; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D014615:Vaccinia / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D014616:Vaccinia virus / Q000187:drug effects* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir