Abstract Title:

Antiviral activity of 3(2H)- and 6-chloro-3(2H)-isoflavenes against highly diverged, neurovirulent vaccine-derived, type2 poliovirus sewage isolates.

Abstract Source:

PLoS One. 2011 ;6(5):e18360. Epub 2011 May 25. PMID: 21904594

Abstract Author(s):

Lester M Shulman, Danit Sofer, Yossi Manor, Ella Mendelson, Jean Balanant, Anna Laura Salvati, Francis Delpeyroux, Lucia Fiore

Article Affiliation:

Central Virology Laboratory, Public Health Services Israel Ministry of Health, Chaim Sheba Medical Center, Tel Hashomer, Israel. lester.shulman@sheba.health.gov.il


BACKGROUND: Substituted 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, aVDPV(2)s, from two unrelated persistent infections were periodically isolated from Israeli sewage.

AIM: To determine whether highly evolved aVDPV(2)s derived from persistent infections retained sensitivity to isoflavenes.

METHODS: Sabin-2 and ten aVDPV(2) 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 aVDPV(2)s was measured in PVR-Tg-21 transgenic mice. Differences were related to unique amino acid substitutions within capsid proteins.

PRINCIPAL FINDINGS: The presence of either flavanoid inhibited viral titers of Sabin-2 and nine of ten aVDPV(2)s by one to two log(10). The tenth aVDPV(2), 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 aVDPV(2)s and all reacquired a full neurovirulent phenotype except one with amino acid substitutions flanking the VP1 site.

CONCLUSION: Both isoflavenes worked equally well against Sabin 2 and most of the highly-diverged, Israeli, aVDPV(2)s 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.

Study Type : Transgenic Animal Study
Additional Links
Pharmacological Actions : Antiviral Agents : CK(1957) : AC(1034)

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Sayer Ji
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