Summary auto-generated
Researchers studied antigenic variation in foot-and-mouth disease virus (FMDV) during passage in cell culture without immune selection pressure. They serially passaged FMDV clone C-S8c1 in cultured cells and analyzed mutations at different antigenic sites (A, C, and D) on the viral capsid. Mutation frequencies at sites C and D were more than 20-fold lower than at site A, indicating differential constraints on variation at different antigenic regions. While site A showed frequent amino acid substitutions, particularly at two hypervariable positions in the VP1 protein, sites C and D showed severe restrictions to mutation fixation. Despite these genetic restrictions at sites C and D, neutralization assays using polyclonal antibodies revealed that antigenic variation occurred at epitopes unrelated to site A without immune pressure. The findings support a "random change model" where tolerated mutations at antigenically important sites can become fixed through stochastic processes and quasispecies dynamics, independent of antibody selection. This demonstrates that antigenic variation in RNA viruses is not exclusively driven by immune selection but can result from structural and functional constraints that permit variation at some epitopes more readily than others.
Key findings
- Mutation frequencies at antigenic sites C and D were >20-fold lower than at site A despite passage without immune selection
- Site A showed frequent amino acid substitutions at hypervariable regions in the VP1 G-H loop, while sites C and D showed severe restrictions to genetic variation
- Despite genetic constraints, antigenic variation was detected at epitopes unrelated to site A through polyclonal antibody neutralization assays
- Different antigenic sites tolerate amino acid substitutions at different rates depending on structural and functional constraints of the viral capsid
- Antigenic variation can occur through stochastic fixation of tolerated mutations independent of antibody-mediated immune selection
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Abstract
Clonal populations of foot-and-mouth disease virus have been serially passaged in cell culture to analyse variation in the absence of immune selection at different antigenic sites of the virus. Mutant frequencies at the RNA regions encoding two independent antigenic sites (sites C and D) were more than twentyfold lower than for antigenic site A (the G- H loop of VP1). Correspondingly, fixation of amino acid substitutions was very restricted in sites C and D. In spite of such a restriction, neutralization assays using fractionated anti-virus polyclonal antibodies has provided direct evidence of significant antigenic variation in the absence of immune selection at sites unrelated to site A. It is proposed that the degree of tolerance to acceptance of amino acid replacements may modulate the variation at different antigenic epitopes of the same virus.