Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention
Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention
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DOI：
10.1073/pnas.0703498104
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发表时间：
2007-05-29
影响因子：
11.1
通讯作者：
Lai, Ching-Juh
中科院分区：
文献类型：
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作者：
Goncalvez, Ana P.;Engle, Ronald E.;Lai, Ching-Juh
登革病毒（DENV）或任何其他黄病毒感染会诱导产生交叉反应性的抗体，但这些抗体中和能力弱或无中和能力，它们能识别包膜糖蛋白中涉及融合肽的表位。源自黑猩猩的人源化单克隆抗体IgG 1A5具有交叉反应性抗体的特性。单克隆抗体IgG 1A5在体外多种带有Fc受体的细胞中通过抗体依赖增强作用（ADE）机制上调登革病毒感染。在一系列亚中和浓度的IgG 1A5条件下，观察到K562细胞中病毒产量根据登革病毒血清型的不同增加了10到1000倍。在幼年恒河猴中，用被动转移的IgG 1A5稀释液免疫后，也证明登革病毒 - 4病毒血症滴度显著增加（高达100倍）。这些结果，连同先前关于多克隆血清对登革病毒 - 2感染的抗体依赖增强作用的发现，建立了用于分析抗体依赖增强作用的灵长类动物模型。考虑到这些交叉反应性抗体的大量存在，我们的观察结果证实，在先前感染过或具有母体传递免疫力的人类感染登革病毒期间，可能会发生显著的病毒扩增，从而可能导致重症登革热。通过改变负责与Fc受体结合的抗体Fc结构，探索了消除抗体依赖增强作用的策略。IgG 1A5变体包含来自IgG2或IgG4抗体Fc区域的氨基酸替换，其降低但未消除在K562细胞中对登革病毒 - 4的增强活性。重要的是，Fc区域CH2结构域N末端的9个氨基酸缺失消除了增强活性。
Infection with dengue virus (DENV) or any other flavivirus induces cross-reactive, but weakly neutralizing or nonneutralizing, antibodies that recognize epitopes involving the fusion peptide in the envelope glycoprotein. Humanized mAb IgG 1A5, derived from a chimpanzee, shares properties of cross-reactive antibodies. mAb IgG 1A5 up-regulated DENV infection by a mechanism of antibody-dependent enhancement (ADE) in a variety of Fc receptor-bearing cells in vitro. A 10- to 1,000-fold increase of viral yield in K562 cells, dependent on the DENV serotype, was observed over a range of subneutralizing concentrations of IgG 1A5. A significant increase of DENV-4 viremia titers (up to 100-fold) was also demonstrated in juvenile rhesus monkeys immunized with passively transferred dilutions of IgG 1A5. These results, together with earlier findings of AIDE of DENV-2 infection by a polyclonal serum, establish the primate model for analysis of ADE. Considering the abundance of these cross-reactive antibodies, our observations confirm that significant viral amplification could occur during DENV infections in humans with prior infection or with maternally transferred immunity, possibly leading to severe dengue. Strategies to eliminate ADE were explored by altering the antibody Fc structures responsible for binding to Fc receptors. IgG 1A5 variants, containing amino acid substitutions from the Fc region of IgG2 or IgG4 antibodies, reduced but did not eliminate DENV-4-enhancing activity in K562 cells. Importantly, a 9-aa deletion at the N terminus of the CH2 domain in the Fc region abrogated the enhancing activity.