Role of mutations G-480 and C-6203 in the attenuation phenotype of Sabin type 1 poliovirus

Abstract

Of the 55 point mutations which distinguish the type 1 poliovirus vaccine strain (Sabin 1) from its neurovirulent progenitor (P1/Mahoney), two have been strongly implicated by previous studies as determinants of the attenuation phenotype. A change of an A to a G at position 480, located within the 5 noncoding region, has been suggested to be the major attenuating mutation, analogous to the mutations at positions 481 and 472 in poliovirus types 2 and 3, respectively. In addition, the change of a U to a C at position 6203, resulting in an amino acid change in the polymerase protein 3D, has also been implicated as a determinant of attenuation, albeit to a lesser extent. To assess the contributions of these mutations to attenuation and temperature sensitivity, reciprocal changes were generated at these positions in infectious cDNA clones of Sabin 1 and P1/Mahoney. Assays in tissue culture and primates indicated that the two mutations make some contribution to the temperature sensitivity of the Sabin 1 strain but that neither is a strong determinant of attenuation.

Comparison of the Neurovirulence of a Vaccine and a Wild-Type Mumps Virus Strain in the Developing Rat Brain

“…Although alterations in similarly functioning proteins of many other RNA viruses (3,20,21,31,37,55,66,67) have been linked to altered virulence, it is unlikely that any single gene is solely responsible for the neurovirulence potential of the virus. In fact, mutations in other coding and noncoding regions have also been linked to altered neurovirulence (6,15,23,33,39,43,49,60,62). The development of a clinically predictive model of mumps virus neurovirulence may allow for these and other changes at the molecular level to be evaluated in a biological disease model.…”

Oral Poliovirus Vaccine Evolution and Insights Relevant to Modeling the Risks of Circulating Vaccine‐Derived Polioviruses (cVDPVs)

“…These studies characterized mutations conferring attenuation of neurovirulence and/or increased temperature sensitivity, which correlates with attenuation, throughout the genome (e.g., nt 21 (5 -UTR), 189 (5 -UTR), 480 (5 -UTR), 935 (VP4-65), 2438 (VP3-225), 2795 (VP1-106), 2879 (VP1-134), 6203 (3D-73), 7441 (3 -UTR)) and identified the mutation at nt position 480 as one of the most critical, although the degree to which each potential attenuating mutation influences neurovirulence remains unclear. (77,81,82,97,111) Several studies show that some of the attenuating mutations of OPV1 revert in primary vaccine recipients over the period of excretion, although reversion at nt position 480, which can occur by direct reversion or by a compensating substitution at nt position 525, varies with respect to the proportion of primary vaccine recipients and time in different studies. (18,79,112) The virus strains isolated from type 1 VAPP cases also show the reversion of several attenuating mutations, most notably at nt position 480.…”

Dual Stem Loops within the Poliovirus Internal Ribosomal Entry Site Control Neurovirulence

“…These studies led to the notion that domain V of the PV IRES is a major determinant of neurovirulence, but the mechanism remained unsolved. The contribution to att of these IRES mutations relative to mutations downstream of the IRES (the open reading frame [ORF] of the polyprotein) has been recently a matter of debate; however, the importance of the viral capsid in the expression of the att phenotype of the Sabin strains has been stressed (5,23).…”