The 5′ untranslated region as a pathogenicity determinant of Semliki Forest virus in mice

An investigation of the role of the 5' untranslated region (UTR) of Semliki Forest virus (SFV) in determining pathogenicity in infected mice was carried out by constructing 5' UTR chimeras. Analysis of 5' UTR sequences showed nucleotide differences between virulent and avirulent strains at positions 21, 35 and 42. Reciprocal chimeras incorporating these changes were constructed from avirulent CA7 and rA7[74], and virulent SFV-4 virus, derived from infectious clones, and avirulent A7 and A7[74] plaque-purified stock virus. Survival rates and neuropathology in intranasally (i.n.) infected mice were analysed. While no statistically significant difference between rates of RNA synthesis was detected between strains in cell culture, an increase in survival of infected mice and a reduction in the severity of brain lesions was observed on substitution of the 5' UTR from a stock avirulent virus into an infectious clone where the remainder of the genome was derived from avirulent virus. However, substitution of a 5' UTR from an avirulent stock virus into an infectious clone where the remainder of the genome was from virulent virus did not affect virulence. These results and other studies suggest that control of virulence is polygenic, and that the SFV 5' UTR acts as a pathogenicity determinant in synergy with other determinants in the genome.