Most of the small number of cases of poliomyelitis which occur in countries where Sabin's attenuated poliovirus vaccines are used are temporally associated with administration of vaccine and involve polioviruses of types 2 and 3 (ref. 1). Recent studies have provided convincing evidence that the Sabin type 2 and 3 viruses themselves may revert to a neurovirulent phenotype on passage in man. We report here that a point mutation in the 5' noncoding region of the genome of the poliovirus type 3 vaccine consistently reverts to wild type in strains isolated from cases of vaccine-associated poliomyelitis. Virus with this change is rapidly selected on passage through the human gastrointestinal tract. The change is associated with a demonstrable increase in the neurovirulence of the virus.

Human T-cell leukaemia viruses (HTLVs) have genomic organization distinct from that of other replication-competent retroviruses, possessing four genes, gag, pol, env and chi. The unique fourth gene, chi (also referred to as lor), is located between env and the 3' long terminal repeat (LTR), encoding a protein of relative molecular mass 40,000 for HTLV-I and 37,000 for HTLV-II, located in the nucleus of infected cells. HTLV-I is the causative agent of adult T-cell leukaemia (ATL), a T-lymphocyte malignancy, while HTLV-II has been found associated with a T-cell variant of hairy cell leukaemia. Both viruses immortalize T cells in vitro. However, the mechanism of cellular transformation induced by HTLV is not known as there seems to be no common site of provirus integration in primary ATL cells and the virus contains no classical oncogene sequences. These observations have provoked speculation that the unique and strongly conserved chi protein (85% amino-acid homology between HTLV-I and -II) is involved in HTLV leukaemogenesis. Recent mutagenesis experiments in our laboratory have shown that the chi gene is essential for HTLV replication. It has also has been shown that the LTRs of HTLV and the related bovine leukaemia virus (BLV) are activated in trans in virus-infected cells, and, although such experiments did not directly demonstrate a role for the chi protein in transcriptional activation, it has been suggested that the chi protein is responsible for the transcriptional activation of the LTR and may be involved in cellular transformation. We have now developed a transient co-transfection assay which demonstrates that transcriptional activation of the HTLV LTR is mediated solely by the chi protein and that no other virus genes are required.

We have determined a major antigenic site for virus neutralization on the capsid protein VP1 of poliovirus type 3. Antigenic mutant viruses selected for resistance to individual monoclonal antibodies had point mutations concentrated in a region 277-294 bases downstream from the start of the region of viral RNA coding for VP1. These findings provide the basis for an improved understanding of the molecular basis of virus neutralization.

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The complete nucleotide sequence has been determined of a strain of poliovirus type 3, P3/119, isolated from the central nervous system of a victim of fatal vaccine-associated poliomyelitis. Comparison of this sequence with those obtained previously for the Sabin type 3 vaccine, P3/Leon 12a1b and its neurovirulent progenitor, P3/Leon/37, reveals that these three strains are on a direct geneaological lineage and therefore that P3/119 is a bona fide revertant of the vaccine. P3/119 differs in sequence from its attenuated vaccine parent at just seven positions. Only one of these differences, a mutation from U to C at position 472 in the presumed noncoding region of the genome, is a back mutation to the wild type sequence. Of the six other differences, three give rise to coding changes in virus structural proteins, two are silent changes in the major open reading frame of the genome and one affects the 3'-terminus just prior to the poly A tract. These differences indicate that there are three possible types of molecular change which could, singly or collectively, result in attenuation and reversion to neurovirulence of the Sabin type 3 vaccine.