ANALYSIS OF FLAVIVIRUS ENVELOPE PROTEINS REVEALS VARIABLE DOMAINS THAT REFLECT THEIR ANTIGENICITY AND MAY DETERMINE THEIR PATHOGENESIS

Studies on the molecular basis of flavivirus neutralisation, attenuati on and tropism indicate that amino acid substitutions, in different pa rts of the envelope gene, may be responsible for the altered phenotype s. However, the association of particular substitutions with individua l characteristics has proven difficult. Comparative analysis of all kn own tick-borne flavivirus envelope proteins through sequence alignment and a sliding window, reveals clusters of amino acid variation distri buted throughout the envelope protein coding region. Further compariso n with mosquito-borne flaviviruses reveals essentially the same profil e of variability throughout the envelope protein sequence although the re is a major difference within the postulated B domain of these virus es which may reflect their different evolutionary development. Most ph enotypically variant properties, such as serotypic differences, varian ts characteristic of vaccine strains, altered tropisms and neutralisat ion escape mutants, map within the variable clusters. Thus, we propose that natural mutagenesis and selection may occur at specific sites th at do not destroy the secondary and tertiary E protein structure and t hat the variable clusters represent the exposed surface amino acids of the envelope protein defining antigenicity, tropicity and pathogenesi s.