Epistasis and pleiotropy constrain the evolution of cross-reactive breadth in a broadly neutralizing influenza antibody.

IF 7.2 1区生物学 Q1 Agricultural and Biological Sciences

PLoS Biology Pub Date : 2026-09-28 eCollection Date: 2026-09-01 DOI:10.1371/journal.pbio.3004021

Katrine E Dailey, Yiquan Wang, Qi Wen Teo, Chaoyang Wang, Huibin Lv, Ruipeng Lei, Meixuan Tong, Lucia A Rodriguez, Letianchu Wang, Nicholas C Wu

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引用次数: 0

Abstract

The highly conserved influenza virus hemagglutinin (HA) stem domain is a major target for broadly neutralizing antibodies (bnAbs). However, despite being discovered more than a decade ago, the IGHV1-69-encoded CR9114 remains the only HA stem bnAb that cross-reacts with both influenza A and B viruses. To investigate the constraints on the breadth evolution of CR9114, this study performs four deep mutational scanning experiments to compare the binding affinity landscapes of the germline and somatic CR9114 against H1 HA, H3 HA, and influenza B virus HA. Many mutations that minimally affect or even improve the H1 HA binding are detrimental for binding to H3 HA and influenza B virus HA. We further reveal the prevalence of epistasis in IGHV1-69 HA stem bnAbs. Overall, our findings provide a mechanistic explanation for the scarcity of HA stem bnAbs with cross-reactivity against both influenza A and B viruses, and have important implications for developing broadly protective influenza vaccines.

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上位性和多效性限制了广泛中和流感抗体交叉反应宽度的演变。

高度保守的流感病毒血凝素（HA）茎结构域是广泛中和抗体（bnAbs）的主要靶点。然而，尽管早在十多年前就被发现，ighv1 -69编码的CR9114仍然是唯一能与甲型流感病毒和乙型流感病毒发生交叉反应的HA干细胞bnAb。为了研究CR9114宽度进化的制约因素，本研究进行了四次深度突变扫描实验，比较了种系和体细胞CR9114对H1 HA、H3 HA和乙型流感病毒HA的结合亲和力。许多对H1血凝素结合影响最小甚至改善的突变对H3血凝素和乙型流感病毒血凝素的结合是有害的。我们进一步揭示了IGHV1-69 HA干细胞bnab的上位性。总的来说，我们的研究结果为缺乏对甲型和乙型流感病毒具有交叉反应性的HA干细胞bnab提供了机制解释，并对开发具有广泛保护性的流感疫苗具有重要意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

PLoS Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOLOGY

CiteScore

15.40

自引率

2.00%

发文量

359

审稿时长

3-8 weeks

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