Lien vers Pubmed [PMID] – 8392604
J. Virol. 1993 Aug;67(8):4630-8
The attenuated Sabin strain of poliovirus type 1 (PV-1) differs from the neurovirulent PV-1 Mahoney strain by 55 nucleotide mutations. Only one of these mutations (A-480–>G, in the 5′ noncoding (5′ NC) region of the genome, is well characterized, and it confers a strong attenuating effect. We attempted to identify genetic attenuation determinants in the 3′-terminal part of the Sabin 1 genome including the 3D polymerase (3Dpol) gene and the 3′ NC region. Previous studies suggested that some of the 11 mutations in this region of the Sabin 1 genome, and in particular a mutation in the polymerase gene (U-6203–>C, Tyr-73–>His), are involved to some extent in the attenuation of PV-1. We analyzed the attenuating effect in the mouse model by using the mouse-adapted PV-1/PV-2 chimeric strain v510 (a Mahoney strain carrying nine amino acids of the VP1 capsid protein from the Lansing strain of PV-2). Mutagenesis of locus 6203 was performed on the original v510 (U-6203–>C) and also on a hybrid v510/Sabin 1 (C-6203–>U) carrying the downstream 1,840 nucleotides of the Sabin 1 genome including the 3Dpol and 3′ NC regions. Statistical analysis of disease incidence and time to disease onset in numerous mice inoculated with these strains strongly suggested that nucleotide C-6203 is involved in the attenuation of the Sabin 1 strain. Results also suggested that, among the mutations located in the 3Dpol and 3′ NC regions, nucleotide C-6203 may be the principal or the only one to be involved in attenuation in this mouse model. We also found that the effect of C-6203 was weaker than that of nucleotide G-480; the two nucleotides acted independently and may have a cumulative effect on attenuation. The U-6203–>C substitution also appeared to contribute to the thermosensitivity of the Sabin 1 strain.