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Nature:增强新生儿Fc受体功能提高灵长类抗SHIV感染能力

标签:HIV bNAb VRC01 SHIV 猴子
摘要 : 美国国立卫生研究院领导的一个科学家小组发现,低剂量的抗HIV bNAb——VRC01突变能够比低剂量输注未突变VRC01可更有效地保护猴子防止SHIV感染。这项研究成果可能表明基于抗体的预防策略不仅可对抗HIV,也适用于在粘膜表面侵入人体的其他一些病毒。相关文章发表于2014年8月13日的《Nature》杂志上。
图示:VRC01的阴道组织定位和积累

图示:VRC01的阴道组织定位和积累

近年来,科学家们一直在追求将注射或静脉内输注bNAbs作为一种预防HIV感染的策略。研究证实,这一称作为被动免疫的技术可以保护猴子免受猴人类免疫缺陷病毒(SHIV)的感染。为了让被动免疫成为广泛可行的人类HIV预防方案,科学家们希望能够改造一些bNAbs,使得每隔几个月只需给予少量的bNAbs。

为此,由美国国立卫生研究院领导的一个科学家小组突变了强有力的抗HIV bNAb——VRC01,在注入到猴子体内后,相比于未突变的VRC01它在血液中持续存在的时间要长3倍,此外,它还集中于直肠粘膜组织中,在那里相比于未突变的VRC01持续存留时间长2倍。抗HIV bNAbs集中于直肠和阴道的粘膜表面,对阻断HIV性传播至关重要。

此外,科学家们还发现低剂量输注突变的VRC01相比于低剂量输注未突变VRC01可更有效地保护猴子防止SHIV感染。

突变增强了VRC01与一种细胞蛋白结合的能力,由此阻止了细胞内的抗体降解,影响了抗体到达粘膜表面并停留在那里的频率。这一研究结果有可能表明了,基于抗体的预防策略不仅可对抗HIV,也适用于在粘膜表面侵入人体的其他一些病毒,例如轮状病毒、脊髓灰质炎病毒、诺如病毒和流感病毒。

下一步,研究人员将在人类中测试输注突变VRC01,以了解它是否能够集中于粘膜组织中,并在更长的时间里持续存在于粘膜组织和血液中。

原文摘要:

Enhanced neonatal Fc receptor function improves protection against primate SHIV infection

Sung-Youl Ko, Amarendra Pegu, Rebecca S. Rudicell, Zhi-yong Yang, M. Gordon Joyce,Xuejun Chen, Keyun Wang, Saran Bao, Thomas D. Kraemer, Timo Rath, Ming Zeng,Stephen D. Schmidt, John-Paul Todd, Scott R. Penzak, Kevin O. Saunders, Martha C. Nason, Ashley T. Haase, Srinivas S. Rao, Richard S. Blumberg, John R. Mascola & Gary J. Nabel

To protect against human immunodeficiency virus (HIV-1) infection, broadly neutralizing antibodies (bnAbs) must be active at the portals of viral entry in the gastrointestinal or cervicovaginal tracts. The localization and persistence of antibodies at these sites is influenced by the neonatal Fc receptor (FcRn), whose role in protecting against infection in vivo has not been defined. Here, we show that a bnAb with enhanced FcRn binding has increased gut mucosal tissue localization, which improves protection against lentiviral infection in non-human primates. A bnAb directed to the CD4-binding site of the HIV-1 envelope (Env) protein (denoted VRC01)3 was modified by site-directed mutagenesis to increase its binding affinity for FcRn. This enhanced FcRn-binding mutant bnAb, denoted VRC01-LS, displayed increased transcytosis across human FcRn-expressing cellular monolayers in vitro while retaining FcγRIIIa binding and function, including antibody-dependent cell-mediated cytotoxicity (ADCC) activity, at levels similar to VRC01 (the wild type). VRC01-LS had a threefold longer serum half-life than VRC01 in non-human primates and persisted in the rectal mucosa even when it was no longer detectable in the serum. Notably, VRC01-LS mediated protection superior to that afforded by VRC01 against intrarectal infection with simian–human immunodeficiency virus (SHIV). These findings suggest that modification of FcRn binding provides a mechanism not only to increase serum half-life but also to enhance mucosal localization that confers immune protection. Mutations that enhance FcRn function could therefore increase the potency and durability of passive immunization strategies to prevent HIV-1 infection.

来源: Nature 浏览次数:102

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