In Vivo Evaluation of the Cross-Genotype Neutralizing Activity of Polyclonal Antibodies Against Hepatitis C Virus
In Vivo Evaluation of the Cross-Genotype Neutralizing Activity of Polyclonal Antibodies Against Hepatitis C Virus
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DOI：
10.1002/hep.24171
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发表时间：
2011-03-01
期刊：
影响因子：
13.5
通讯作者：
Leroux-Roels, Geert
中科院分区：
文献类型：
--
作者：
Meuleman, Philip;Bukh, Jens;Leroux-Roels, Geert
丙型肝炎病毒(丙型肝炎病毒)感染的控制仍然是具有全球医学重要性的巨大挑战。利用各种体外方法，已在急性和慢性丙型肝炎患者中鉴定出中和抗体(NAB)，这些中和抗体在解决急性丙型肝炎病毒感染中的确切作用仍不清楚。我们之前已经证明，从2003年从慢性丙型肝炎患者(患者H)的血浆中分离出来的纯化多克隆抗体可以保护人肝嵌合小鼠免受1977年从患者H(H77)分离的自体丙型肝炎病毒株的攻击。在这项研究中，我们研究了从2006年(H06)患者H分离的多克隆抗体，这些多克隆抗体在丙型肝炎病毒伪粒子(HCVpp)和丙型肝炎病毒细胞培养(HCVcc)系统中都显示出高的跨基因中和活性，是否也能够预防体内不同基因型(GT)的丙型肝炎病毒感染。在h06抗体被动免疫后，嵌合小鼠被H77C(GT1a)、ED43(Gt4a)或HK6a(Gt6a)共同菌株攻击。根据先前的结果，h06-抗体阻止了嵌合小鼠感染自体病毒。然而，同源挑战的结果很大程度上受注入的挑战病毒数量的影响。根据所使用的病毒基因型，h06-抗体能够保护多达50%的嵌合小鼠免受异源挑战。抗体预处理失败的动物表现出明显的病毒感染动力学延迟。对回收的病毒进行的序列分析没有表明抗体导致了病毒逃逸。结论：从慢性丙型肝炎患者体内分离的抗丙型肝炎病毒多克隆抗体可以抵抗不同丙型肝炎病毒的体内攻击。然而，跨基因中和抗体的体内保护效果低于细胞培养实验预测的效果。(《肝病》2011；53：755-762)
Control of hepatitis C virus (HCV) infection remains a huge challenge of global medical importance. Using a variety of in vitro approaches, neutralizing antibodies (nAbs) have been identified in patients with acute and chronic hepatitis C. The exact role these nAbs play in the resolution of acute HCV infection still remains elusive. We have previously shown that purified polyclonal antibodies isolated from plasma obtained in 2003 from a chronic HCV patient (Patient H) can protect human liver chimeric mice from a subsequent challenge with the autologous HCV strain isolated from Patient H in 1977 (H77). In this study we investigated whether polyclonal antibodies isolated from Patient H in 2006 (H06), which display high cross-genotype neutralizing activity in both the HCV pseudoparticle (HCVpp) and HCV cell culture (HCVcc) systems, were also able to prevent HCV infection of different genotypes (gt) in vivo. Following passive immunization with H06-antibodies, chimeric mice were challenged with the consensus strains H77C (gt1a), ED43 (gt4a), or HK6a (gt6a). In accordance with previous results, H06-antibodies prevented infection of chimeric mice with the autologous virus. However, the outcome of a homologous challenge is highly influenced by the amount of challenge virus injected. Depending on the viral genotype used, H06-antibodies were able to protect up to 50% of chimeric mice from a heterologous challenge. Animals in which the antibody pretreatment failed displayed a clear delay in the kinetics of viral infection. Sequence analysis of the recovered viruses did not suggest antibody-induced viral escape. Conclusion: Polyclonal anti-HCV antibodies isolated from a chronic HCV patient can protect against an in vivo challenge with different HCV genotypes. However, the in vivo protective efficacy of cross-genotype neutralizing antibodies was less than predicted by cell culture experiments. (HEPATOLOGY 2011;53:755-762)