The efficacy of cidofovir treatment of mice infected with ectromelia (mousepox) virus encoding interleukin-4.
Improved vaccines and therapies for virulent poxvirus infection are required, particularly in the light of recent threats of bioterrorism. Cidofovir (HPMPC) is an acyclic nucleoside analog with proven efficacy against poxviruses. Here, we evaluated HPMPC in mice given a recombinant ectromelia virus (ECTV) encoding interleukin-4 (ECTV-IL-4) that is highly immune suppressive. Mousepox-sensitive BALB/c mice given HPMPC for five consecutive days after infection were protected against the lethal effects of a control ECTV recombinant, although they suffered a chronic form of mousepox disease. High doses of the drug resulted in a milder localized disease. In contrast, HPMPC failed to protect mousepox-resistant C57BL/6 mice against ECTV-IL-4, although its lethal effects were delayed by five daily doses of 20 mg/kg or a single dose of 100 mg/kg. Higher daily doses further delayed mortality, although the majority of animals eventually succumbed to infection. It appears that HPMPC inhibited ECTV-IL-4 replication without clearance, with the virus having a lethal effect when the drug was removed. Resistance of ECTV-IL-4 to HPMPC treatment may relate to the virus's ability to inhibit antiviral cell-mediated immunity. Interestingly, ECTV-IL-4-mediated immune suppression was not accompanied by a reduction in systemic IFN-gamma expression, suggestive of an alternative or highly localized suppressive mechanism.
Robbins
Samantha J
SJ
Division of Immunology and Genetics, John Curtin School of Medical Research, P.O. Box 334, Canberra, ACT 2601, Australia.
Jackson
Ronald J
RJ
Fenner
Frank
F
Beaton
Sandra
S
Medveczky
Jill
J
Ramshaw
Ian A
IA
Ramsay
Alistair J
AJ
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004481:Ectromelia virus / Q000187:drug effects / Q000276:immunology*; D004482:Ectromelia, Infectious / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*
D000998:Antiviral Agents; D063065:Organophosphonates; D015847:Interleukin-4; D003596:Cytosine; D000077404:Cidofovir