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.

Frank MacFarlane Burnet: two personal views.

In honor of the fiftieth anniversary of Frank MacFarlane Burnet's presentation of the clonal selection theory, two of his former staff reminisce about their interactions with this Nobel prize-winning scientist.

Biological agents as weapons 1: smallpox and botulism.

1. Early recognition by clinicians of illnesses suggesting a biological attack is integral to the public health response. 2. The four biological agents of most concern are smallpox virus, botulinum toxin, and anthrax and plague bacteria. 3. Smallpox is distinguishable from chickenpox by the prominent prodromal period and lesions that develop at the same pace and, on any part of the body, appear identical to each other, evolve slowly and are peripherally distributed. 4. The degree of protection conferred by smallpox vaccination given 20 or more years ago is unknown. 5. Foodborne and inhalational botulism could result from deliberate release of toxin. 6. Botulism presents with cranial nerve palsies and descending paralysis in a patient with normal conscious state and no fever.

Biological agents as weapons 2: anthrax and plague.

Although most naturally occurring infections with anthrax and plague are cutaneous, both organisms are most likely to be deliberately disseminated in aerosolised form, resulting in severe pulmonary illness. Mortality from both would be high and rapid in the absence of early and effective treatment, making swift and effective liaison between alert clinicians and public health authorities crucial to an effective response. Differentiating features include mediastinal widening (anthrax) and haemoptysis (plague). Doxycycline and ciprofloxacin are effective agents for prophylaxis and treatment for both diseases. Medical advocacy for strengthening the Biological Weapons Convention, particularly with an enforceable protocol including verification and compliance provisions, is needed.