EVOLUTION OF THE SABIN TYPE-1 POLIOVIRUS IN HUMANS - CHARACTERIZATIONOF STRAINS ISOLATED FROM PATIENTS WITH VACCINE-ASSOCIATED PARALYTIC POLIOMYELITIS

Attenuated strains of the Sabin oral poliovirus vaccine replicate in t he human gut and in rare cases causes vaccine-associated paralytic pol iomyelitis (VAPP). Reversion of vaccine strains toward a pathogenic ph enotype is probably one of the main causes of VAPP, a disease most fre quently associated with type 3, and type 2 strains and more rarely wit h the type 1 (Sabin 1) strain. To identify the determinants and mechan isms of safety versus pathogenicity of the Sabin 1 strain, we characte rized the genetic and phenotypic changes in six Sabin 1-derived viruse s isolated from immunocompetent patients with VAPP. The genomes of the se strains carried either few or numerous mutations from the original Sabin 1 genome. As assessed in transgenic mice carrying the human poli ovirus receptor (PVR-Tg mice), all but one strain had lost the attenua ted phenotype. Four strains presented only a moderate neurovirulent ph enotype, probably due at least in part to reversions to the wild-type genotype, which were detected in the 5' noncoding region of the genome . The reversions found in most strains at nucleotide position 480, are known to be associated with an increase in neurovirulence. The constr uction and characterization of Sabin 1 mutants implicated a reversion at position 189, found in one strain, in the phenotypic change. The pr esence of 71 mutations in one neurovirulent strain suggests that a vac cine-derived strain can survive for a long time in humans. Surprisingl y, none of the strains analyzed were as neurovirulent to PVR-Tg mice a s was the wild-type parent of Sabin 1 (Mahoney) or a previously identi fied neurovirulent Sabin 1 mutant selected at a high temperature in cu ltured cells. Thus, in the human gut, the Sabin 1 strain does not nece ssarily evolve toward the genetic characteristics and high neuropathog enicity of its wild-type parent.