Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox, and Vaccinia Viruses

• DOI: 10.1128/aac.46.5.1329-1335.2002
• Publication Date: 2002-07-27T10:09:01Z
• Authors: Donald F. Smee; Robert W. Sidwell; Debbie Kefauver; Mike Bray; John W. Huggins
• Keywords: Cowpox; Cowpox virus; Poxviridae; Cidofovir; Orthopoxvirus

ABSTRACT Cidofovir {[( S )-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] [HPMPC]}-resistant forms of camelpox, cowpox, monkeypox, and vaccinia viruses were developed by prolonged passage in Vero 76 cells the presence drug. Eight- to 27-fold-higher concentrations cidofovir required inhibit resistant than needed wild-type (WT) viruses. Resistant characterized determining their cross-resistance other antiviral compounds, examining different replication abilities two cell lines, studying biochemical basis drug resistance, assessing degrees virulence mice. These cross cyclic HPMPC and, with exception virus, ( )-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine. Three four cowpox monkeypox exhibited reduced infect replicate 3T3 compared cells. Compared WT virus polymers DNA polymerase was 8.5-fold less sensitive inhibition diphosphate, active form Intracellular phosphorylation [ 3 H]cidofovir not stimulated or inhibited infection virus. In intranasally infected BALB/c mice, 80-fold more virulent treatment (100 mg/kg body weight, given one time only as early 5 min after challenge) a could protect mice from mortality. However, prevented mortality 80 100% treated single 100-mg/kg dose at 1, 2, 3, 4 days challenge. By application these results human orthopoxvirus infections, it is anticipated that may be untreatable but attenuated. Studies will need conducted cidofovir-resistant monkeys further support hypotheses.