A cross-neutralizing antibody between HIV-1 and influenza virus.
A cross-neutralizing antibody between HIV-1 and influenza virus.
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HIV-1和流感病毒之间的交叉中和抗体。
DOI：
10.1371/journal.ppat.1009407
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Wilson IA
中科院分区：
文献类型：
--
作者：
Lee CD;Watanabe Y;Wu NC;Han J;Kumar S;Pholcharee T;Seabright GE;Allen JD;Lin CW;Yang JR;Liu MT;Wu CY;Ward AB;Crispin M;Wilson IA
不断的抗原进化使得流感病毒能够在人群中持续存在和传播。作为免疫反应的主要目标，流感病毒上的血凝素 (HA) 表面抗原不断获取并替换 N-连接糖基化位点，以使用宿主衍生的聚糖屏蔽免疫原性蛋白表位。抗聚糖抗体，例如 2G12，以 HIV-1 包膜蛋白 (Env) 为目标，该蛋白的糖基化程度更为广泛，并且在其致密的聚糖屏蔽上含有未加工的寡甘露糖型簇。在此，我们说明 2G12 还可以中和人类季节性甲型流感 H3N2 病毒，这些病毒自 1968 年流感大流行后约 20 年以来已进化为在其 HA 上呈现类似的寡甘露糖型簇。使用结构生物学和质谱方法，我们发现靠近流感血凝素受体结合位点（RBS）的两个 N-糖基化位点代表 2G12 识别的寡甘露糖簇。其中一个聚糖位点在所有人类 H3N2 毒株中高度保守，另一个在病毒进化过程中出现。这两个 N-糖基化位点对于最近的 H3N2 病毒株的适应性也变得至关重要。这些发现揭示了流感病毒聚糖屏蔽的进化，并表明 2G12 样抗体可以作为针对人类包膜病毒的广泛中和剂。从 HIV-1 患者体内分离出广泛中和抗体，为 HIV-1 疫苗的设计提供了宝贵的见解。其中，一组由抗碳水化合物抗体组成，其目标是构成 HIV-1 包膜表面糖蛋白 (Env) 上聚糖屏蔽的 N-聚糖。与HIV-1类似，人类H3N2流感病毒由于过去50年自然进化过程中N-糖基化位点的积累而具有高度糖基化。在这里，我们证明了一种抗 HIV-1 抗体，即 2G12，可以中和过去 35 年的人类 H3N2 病毒。质谱和负染色电子显微镜的综合分析表明，受体结合位点附近两个 N-糖基化位点上的寡甘露糖是 2G12 的目标。值得注意的是，两个聚糖之间的距离和配置与 HIV-1 Env 上的等效寡甘露糖簇相同。此外，突变研究表明，这两个 N-糖基化位点都是最近 H3N2 病毒株生存所必需的。我们的数据表明，如果病毒表面具有足够的密度和分布，2G12 可以通过靶向寡甘露糖来广泛中和非 HIV-1 人类病毒。由于许多病毒表面抗原高度糖基化，因此值得评估 2G12 样抗体作为人类病毒病原体的潜在通用疗法。
Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses. The isolation of broadly neutralizing antibodies from HIV-1 patients has provided valuable insights on the design of HIV-1 vaccines. Among them, one group consisting of anti-carbohydrate antibodies target N-glycans that compose the glycan shield on the Envelope surface glycoprotein (Env) of HIV-1. Similar to HIV-1, human H3N2 influenza viruses are highly glycosylated due to the accumulation of N-glycosylation sites over the past 50 years of natural evolution. Here, we demonstrate that an anti-HIV-1 antibody, namely 2G12, can neutralize human H3N2 viruses from the past 35 years. Comprehensive analyses by mass spectrometry and negative-stain electron microscopy reveal that oligomannose on two N-glycosylation sites near the receptor binding site are the targets of 2G12. Of note, the distance and disposition between the two glycans are the same as the equivalent oligomannose cluster on HIV-1 Env. Furthermore, mutational study shows that these two N-glycosylation sites are both required for survival of the recent H3N2 strains. Our data suggest that 2G12 can broadly neutralize non-HIV-1 human viruses by targeting oligomannose sugars, if of sufficient density and disposition on the viral surface. Since many viral surface antigens are highly glycosylated, it is worth evaluating 2G12-like antibodies as potential general therapeutics for human viral pathogens.
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影响因子：
16.6
作者：
Cao L;Pauthner M;Andrabi R;Rantalainen K;Berndsen Z;Diedrich JK;Menis S;Sok D;Bastidas R;Park SR;Delahunty CM;He L;Guenaga J;Wyatt RT;Schief WR;Ward AB;Yates JR 3rd;Burton DR;Paulson JC
通讯作者：
Paulson JC
影响因子：
64.5
作者：
Garces F;Sok D;Kong L;McBride R;Kim HJ;Saye-Francisco KF;Julien JP;Hua Y;Cupo A;Moore JP;Paulson JC;Ward AB;Burton DR;Wilson IA
通讯作者：
Wilson IA
影响因子：
30.3
作者：
Burton DR;Ahmed R;Barouch DH;Butera ST;Crotty S;Godzik A;Kaufmann DE;McElrath MJ;Nussenzweig MC;Pulendran B;Scanlan CN;Schief WR;Silvestri G;Streeck H;Walker BD;Walker LM;Ward AB;Wilson IA;Wyatt R
通讯作者：
Wyatt R
影响因子：
4.4
作者：
An, Yanming;McCullers, Jonathan A.;Cipollo, John F.
通讯作者：
Cipollo, John F.
影响因子：
5.4
作者：
Abe, Y;Takashita, E;Hongo, S
通讯作者：
Hongo, S