Yu Timothy C, Kikawa Caroline, Dadonaite Bernadeta, Loes Andrea N, Englund Janet A, Bloom Jesse D
Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA.
Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA.
bioRxiv. 2025 May 24:2025.05.24.655919. doi: 10.1101/2025.05.24.655919.
The evolution of human influenza virus hemagglutinin (HA) involves simultaneous selection to acquire antigenic mutations that escape population immunity while preserving protein function and stability. Epistasis shapes this evolution, as an antigenic mutation that is deleterious in one genetic background may become tolerated in another. However, the extent to which epistasis can alleviate pleiotropic conflicts between immune escape and protein function/stability is unclear. Here, we measure how all amino acid mutations in the HA of a recent human H3N2 influenza strain affect its cell entry function, acid stability, and neutralization by human serum antibodies. We find that epistasis has enabled emergence of antigenic mutations that were detrimental to HA's cell entry function in earlier strains. However, epistasis appears insufficient to overcome the pleiotropic costs of antigenic mutations that impair HA's stability, explaining why some mutations that strongly escape human antibodies never fix in nature. Our results refine our understanding of the mutational constraints that shape influenza evolution: epistasis can enable antigenic change, but pleiotropic effects can restrict its trajectory.
人类流感病毒血凝素（HA）的进化涉及同时进行的选择，以获得能够逃避群体免疫的抗原性突变，同时保持蛋白质的功能和稳定性。上位性影响着这种进化，因为在一种遗传背景下有害的抗原性突变在另一种背景下可能会被容忍。然而，上位性能够缓解免疫逃逸与蛋白质功能/稳定性之间多效性冲突的程度尚不清楚。在这里，我们测量了近期人类H3N2流感毒株HA中的所有氨基酸突变如何影响其细胞进入功能、酸稳定性以及被人血清抗体中和的能力。我们发现，上位性使得在早期毒株中对HA细胞进入功能有害的抗原性突变得以出现。然而，上位性似乎不足以克服损害HA稳定性的抗原性突变的多效性代价，这解释了为什么一些能强烈逃避人类抗体的突变在自然界中从未固定下来。我们的结果完善了我们对塑造流感进化的突变限制的理解：上位性能够促成抗原性变化，但多效性效应可能会限制其进化轨迹。
