Mengovirus is a prototypical member of the cardiovirus genus of the family Picornaviridae. The positive-strand RNA genome is 7761 bases in length and encodes a polyprotein of 2293 amino acids. The 5' non-coding region (758 bases) contains an unusual homopolymeric poly(C) tract, which in the wild-type virus, has a sequence of C50UC10. We have discovered through genetic engineering that truncation or deletion of this poly(C) sequence yields infectious virus isolates that grow well in cell culture, but are 10(6) to 10(9) fold less pathogenic to mice than the wild type strain. Animals receiving sublethal doses of the short poly(C) strains characteristically develop high levels of neutralizing antibodies and acquire lifelong protective immunity against challenge with wild type virus. Effectively, the genetically engineered strains are superb vaccines against cardiovirus disease. Moreover, their potential is not limited to murine hosts. Pigs and sub-human primates have also been protectively vaccinated with short poly(C) tract Mengoviruses. The molecular mechanism of poly(C)-mediated pathogenesis is currently under study. Most hypotheses link the activity to induction of the antiviral cytokine, interferon.