Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses.
Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses.
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DOI：
10.1371/journal.ppat.1000350
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发表时间：
2009-03
期刊：
影响因子：
6.7
通讯作者：
Takada A
中科院分区：
文献类型：
--
作者：
Yoshida R;Igarashi M;Ozaki H;Kishida N;Tomabechi D;Kida H;Ito K;Takada A
迄今为止，甲型流感病毒的血凝素 (HA) 已分为 16 个不同的亚型 (H1-H16)。甲型流感病毒的HA亚型主要定义为使用各HA亚型的多克隆抗血清通过中和或血凝抑制试验确定的血清型，其与其他HA亚型几乎没有交叉反应性。因此，一般认为中和抗体在HA亚型之间不具有广泛的交叉反应性。在这项研究中，我们产生了一种新型HA特异性单克隆抗体（MAb），命名为MAb S139/1，它表现出甲型流感病毒的异亚型交叉反应中和和血凝抑制作用。在酶联免疫吸附测定中，发现该 MAb 对许多其他病毒（H1、H2、H3、H5、H9 和 H13 亚型）具有广泛的反应性。我们进一步发现 MAb S139/1 对甲型流感病毒 H1、H2、H3 和 H13 亚型的特定毒株表现出中和和血凝抑制活性。逃脱 MAb S139/1 中和作用的突变病毒选自 A/Aichi/2/68 (H3N2)、A/Adachi/2/57 (H2N2) 和 A/WSN/33 (H1N1) 毒株，对这些逃脱突变体的 HA 基因进行序列分析，揭示了第 156、158 和 193 位（H3 编号）的氨基酸取代。分子模型研究表明，这些氨基酸位于HA的球状头部，并形成与HA受体结合域相邻的新型构象表位。此外，用 MAb S139/1 对小鼠进行被动免疫提供了异亚型保护。这些结果表明，MAb S139/1 与多种 HA 亚型共享的共同抗原位点结合，并通过影响病毒与细胞的附着来中和体外和体内的病毒感染性。本研究支持交叉反应抗体在针对甲型流感病毒感染的异亚型免疫中发挥一定作用的观点，并强调了交叉反应抗体针对流感的潜在治疗效用。中和抗体在预防甲型流感病毒感染方面发挥着关键作用。大多数中和抗体可识别血凝素 (HA)，它是流感病毒的主要表面糖蛋白。 HA 已分为十六种抗原性不同的亚型。由于甲型流感病毒的HA亚型主要定义为通过使用各HA亚型的多克隆抗血清的中和或血凝抑制试验确定的血清型，其与其他HA亚型几乎没有交叉反应性，因此通常认为中和抗体在HA亚型之间不具有广泛的交叉反应性。在此，我们提出了一种新型交叉中和单克隆抗体，该抗体在体外与多种 HA 亚型发生反应，并为小鼠提供针对甲型流感病毒感染的异亚型保护。我们证明该抗体可识别与 HA 受体结合区相邻的共同表位，并抑制病毒与细胞的结合。本研究支持这样的观点，即交叉反应性抗体以及细胞毒性 T 淋巴细胞在针对甲型流感病毒感染的异亚型免疫中发挥一定作用，并强调了交叉反应性单克隆抗体对于甲型流感病毒感染的多价预防和治疗的潜在治疗效用，包括假设的 新的大流行性流感病毒。
The hemagglutinin (HA) of influenza A viruses has been classified into sixteen distinct subtypes (H1–H16) to date. The HA subtypes of influenza A viruses are principally defined as serotypes determined by neutralization or hemagglutination inhibition tests using polyclonal antisera to the respective HA subtypes, which have little cross-reactivity to the other HA subtypes. Thus, it is generally believed that the neutralizing antibodies are not broadly cross-reactive among HA subtypes. In this study, we generated a novel monoclonal antibody (MAb) specific to HA, designated MAb S139/1, which showed heterosubtypic cross-reactive neutralization and hemagglutination inhibition of influenza A viruses. This MAb was found to have broad reactivity to many other viruses (H1, H2, H3, H5, H9, and H13 subtypes) in enzyme-linked immunosorbent assays. We further found that MAb S139/1 showed neutralization and hemagglutination-inhibition activities against particular strains of H1, H2, H3, and H13 subtypes of influenza A viruses. Mutant viruses that escaped neutralization by MAb S139/1 were selected from the A/Aichi/2/68 (H3N2), A/Adachi/2/57 (H2N2), and A/WSN/33 (H1N1) strains, and sequence analysis of the HA genes of these escape mutants revealed amino acid substitutions at positions 156, 158, and 193 (H3 numbering). A molecular modeling study showed that these amino acids were located on the globular head of the HA and formed a novel conformational epitope adjacent to the receptor-binding domain of HA. Furthermore, passive immunization of mice with MAb S139/1 provided heterosubtypic protection. These results demonstrate that MAb S139/1 binds to a common antigenic site shared among a variety of HA subtypes and neutralizes viral infectivity in vitro and in vivo by affecting viral attachment to cells. The present study supports the notion that cross-reactive antibodies play some roles in heterosubtypic immunity against influenza A virus infection, and underscores the potential therapeutic utility of cross-reactive antibodies against influenza. Neutralizing antibodies play a critical role in protection from influenza A virus infection. Most neutralizing antibodies recognize hemagglutinin (HA), which is the major surface glycoprotein of influenza viruses. The HA has been classified into sixteen antigenically distinct subtypes. Since HA subtypes of influenza A viruses are principally defined as serotypes determined by neutralization or hemagglutination inhibition tests using polyclonal antisera to the respective HA subtypes, which have little cross-reactivity to the other HA subtypes, it is generally believed that the neutralizing antibodies are not broadly cross-reactive among HA subtypes. Herein we present a novel cross-neutralizing monoclonal antibody that reacts with a variety of HA subtypes in vitro and provides heterosubtypic protection against influenza A virus infections in mice. We demonstrate that this antibody recognizes a common epitope adjacent to the receptor binding region of HA and inhibits virus binding to the cells. The present study supports the notion that cross-reactive antibodies, as well as cytotoxic T lymphocytes, play some roles in heterosubtypic immunity against influenza A virus infection, and underscores the potential therapeutic utility of cross-reactive monoclonal antibodies for multivalent prophylaxis and treatment against infection with influenza A viruses, including the hypothetical new pandemic influenza viruses.
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影响因子：
14.9
作者：
Eswar, N;John, B;Sali, A
通讯作者：
Sali, A
流感病毒数据库（IVDB）：流感病毒研究的综合信息资源和分析平台。
影响因子：
14.9
作者：
通讯作者：
--
影响因子：
2.7
作者：
Medeiros, R;Naffakh, N;van der Werf, S
通讯作者：
van der Werf, S
影响因子：
5.8
作者：
Hanson BJ;Boon AC;Lim AP;Webb A;Ooi EE;Webby RJ
通讯作者：
Webby RJ
影响因子：
64.5
作者：
CATON, AJ;BROWNLEE, GG;GERHARD, W
通讯作者：
GERHARD, W