The efficacy of cidofovir treatment of mice infected with ectromelia (mousepox) virus encoding interleukin-4

Samantha J. Robbins; Ronald J. Jackson; Frank Fenner; Sandra Beaton; Jill Medveczky; Ian A. Ramshaw; Alistair J. Ramsay

doi:10.1016/j.antiviral.2004.12.003

The efficacy of cidofovir treatment of mice infected with ectromelia (mousepox) virus encoding interleukin-4

Samantha J. Robbins, Ronald J. Jackson^*, Frank Fenner, Sandra Beaton, Jill Medveczky, Ian A. Ramshaw, Alistair J. Ramsay

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

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Abstract

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-γ expression, suggestive of an alternative or highly localized suppressive mechanism.

Original language	English
Pages (from-to)	1-7
Number of pages	7
Journal	Antiviral Research
Volume	66
Issue number	1
DOIs	https://doi.org/10.1016/j.antiviral.2004.12.003
Publication status	Published - Apr 2005

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title = "The efficacy of cidofovir treatment of mice infected with ectromelia (mousepox) virus encoding interleukin-4",

abstract = "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-γ expression, suggestive of an alternative or highly localized suppressive mechanism.",

keywords = "Cidofovir, Immune suppression, Interleukin-4, Mousepox infection",

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AU - Jackson, Ronald J.

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AU - Medveczky, Jill

AU - Ramshaw, Ian A.

AU - Ramsay, Alistair J.

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AB - 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-γ expression, suggestive of an alternative or highly localized suppressive mechanism.

KW - Cidofovir

KW - Immune suppression

KW - Interleukin-4

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The efficacy of cidofovir treatment of mice infected with ectromelia (mousepox) virus encoding interleukin-4

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