Abstract
BackgroundSubstituted flavanoids interfere with uncoating of Enteroviruses including Sabin-2 polio vaccine strains. However flavanoid resistant and dependent, type-2 polio vaccine strains (minimally-diverged), emerged during in vitro infections. Between 1998–2009, highly-diverged (8 to >15%) type-2, aVDPV2s, from two unrelated persistent infections were periodically isolated from Israeli sewage.AimTo determine whether highly evolved aVDPV2s derived from persistent infections retained sensitivity to isoflavenes.MethodsSabin-2 and ten aVDPV2 isolates from two independent Israeli sources were titered on HEp2C cells in the presence and absence of 3(2H)- Isoflavene and 6-chloro-3(2H)-Isoflavene. Neurovirulence of nine aVDPV2s was measured in PVR-Tg-21 transgenic mice. Differences were related to unique amino acid substitutions within capsid proteins.Principal FindingsThe presence of either flavanoid inhibited viral titers of Sabin-2 and nine of ten aVDPV2s by one to two log10. The tenth aVDPV2, which had unique amino acid substitution distant from the isoflavene-binding pocket but clustered at the three- and five-fold axies of symmetry between capsomeres, was unaffected by both flavanoids. Genotypic neurovirulence attenuation sites in the 5′UTR and VP1 reverted in all aVDPV2s and all reacquired a full neurovirulent phenotype except one with amino acid substitutions flanking the VP1 site.ConclusionBoth isoflavenes worked equally well against Sabin 2 and most of the highly-diverged, Israeli, aVDPV2s isolates. Thus, functionality of the hydrophobic pocket may be unaffected by selective pressures exerted during persistent poliovirus infections. Amino acid substitutions at sites remote from the drug-binding pocket and adjacent to a neurovirulence attenuation site may influence flavanoid antiviral activity, and neurovirulence, respectively.
Highlights
Poliovirus is a member of the Picornaviridae
Functionality of the hydrophobic pocket may be unaffected by selective pressures exerted during persistent poliovirus infections
Mutations that interfered with the antiviral activity of these compounds appeared during in vitro replication of type 2 polio vaccine strains in the presence of these compound [4]
Summary
Poliovirus is a member of the Picornaviridae. Like other members of the Picornaviridae, poliovirus RNA is encapsidated in an icosahedral structure with axes of three-fold and five-fold symmetry formed from 60 capsomeres containing one copy each of viral capsid proteins VP1, VP2, VP3 and VP4 [1]. Flavanoids and flavonoids were shown to have antiviral activity in vitro against several picornaviruses including type 2 polioviruses [3,4,5,6,7,8]. These compounds act primarily by occupying the hydrophobic pocket, interfering with virus uncoating. They did not directly affect viral adsorption or RNA synthesis [4]. Between 1998–2009, highly-diverged (8 to .15%) type-2, aVDPV2s, from two unrelated persistent infections were periodically isolated from Israeli sewage
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