Cellular Biology Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Laboratory of Respiratory Viral Diseases, Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Sci Immunol. 2024 Mar 22;9(93):eadj9534. doi: 10.1126/sciimmunol.adj9534.
Antigenic drift, the gradual accumulation of amino acid substitutions in the influenza virus hemagglutinin (HA) receptor protein, enables viral immune evasion. Antibodies (Abs) specific for the drift-resistant HA stem region are a promising universal influenza vaccine target. Although anti-stem Abs are not believed to block viral attachment, here we show that complement component 1q (C1q), a 460-kilodalton protein with six Ab Fc-binding domains, confers attachment inhibition to anti-stem Abs and enhances their fusion and neuraminidase inhibition. As a result, virus neutralization activity in vitro is boosted up to 30-fold, and in vivo protection from influenza PR8 infection in mice is enhanced. These effects reflect increased steric hindrance and not increased Ab avidity. C1q greatly expands the anti-stem Ab viral escape repertoire to include residues throughout the HA, some of which cause antigenic alterations in the globular region or modulate HA receptor avidity. We also show that C1q enhances the neutralization activity of non-receptor binding domain anti-SARS-CoV-2 spike Abs, an effect dependent on spike density on the virion surface. These findings demonstrate that C1q can greatly expand Ab function and thereby contribute to viral evolution and immune escape.
抗原漂移是流感病毒血凝素（HA）受体蛋白中氨基酸取代的逐渐积累，使病毒能够逃避免疫。针对漂移抗性 HA 茎区的抗体（Abs）是一种有前途的通用流感疫苗靶点。尽管人们认为针对茎区的 Abs 不会阻止病毒附着，但在这里我们表明，补体成分 1q（C1q），一种具有六个 Ab Fc 结合结构域的 460 千道尔顿蛋白，赋予针对茎区的 Abs 附着抑制作用，并增强其融合和神经氨酸酶抑制作用。结果，体外病毒中和活性提高了 30 倍，体内对流感 PR8 感染的保护作用增强。这些效应反映了增加的空间位阻，而不是增加的 Ab 亲和力。C1q 极大地扩展了针对茎区的 Ab 病毒逃逸谱，包括整个 HA 中的残基，其中一些残基在球形区域引起抗原改变或调节 HA 受体亲和力。我们还表明，C1q 增强了非受体结合域抗 SARS-CoV-2 刺突 Abs 的中和活性，这种效应依赖于病毒表面刺突密度。这些发现表明，C1q 可以极大地扩展 Ab 的功能，从而促进病毒进化和免疫逃避。
