Zhu Zhongyu, Chakraborti Samitabh, He Yuxian, Roberts Anjeanette, Sheahan Tim, Xiao Xiaodong, Hensley Lisa E, Prabakaran Ponraj, Rockx Barry, Sidorov Igor A, Corti Davide, Vogel Leatrice, Feng Yang, Kim Jae-Ouk, Wang Lin-Fa, Baric Ralph, Lanzavecchia Antonio, Curtis Kristopher M, Nabel Gary J, Subbarao Kanta, Jiang Shibo, Dimitrov Dimiter S
Protein Interactions Group, Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702, USA.
Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12123-8. doi: 10.1073/pnas.0701000104. Epub 2007 Jul 9.
The severe acute respiratory syndrome coronavirus (SARS-CoV) caused a worldwide epidemic in late 2002/early 2003 and a second outbreak in the winter of 2003/2004 by an independent animal-to-human transmission. The GD03 strain, which was isolated from an index patient of the second outbreak, was reported to resist neutralization by the human monoclonal antibodies (hmAbs) 80R and S3.1, which can potently neutralize isolates from the first outbreak. Here we report that two hmAbs, m396 and S230.15, potently neutralized GD03 and representative isolates from the first SARS outbreak (Urbani, Tor2) and from palm civets (SZ3, SZ16). These antibodies also protected mice challenged with the Urbani or recombinant viruses bearing the GD03 and SZ16 spike (S) glycoproteins. Both antibodies competed with the SARS-CoV receptor, ACE2, for binding to the receptor-binding domain (RBD), suggesting a mechanism of neutralization that involves interference with the SARS-CoV-ACE2 interaction. Two putative hot-spot residues in the RBD (Ile-489 and Tyr-491) were identified within the SARS-CoV spike that likely contribute to most of the m396-binding energy. Residues Ile-489 and Tyr-491 are highly conserved within the SARS-CoV spike, indicating a possible mechanism of the m396 cross-reactivity. Sequence analysis and mutagenesis data show that m396 might neutralize all zoonotic and epidemic SARS-CoV isolates with known sequences, except strains derived from bats. These antibodies exhibit cross-reactivity against isolates from the two SARS outbreaks and palm civets and could have potential applications for diagnosis, prophylaxis, and treatment of SARS-CoV infections.
严重急性呼吸综合征冠状病毒（SARS-CoV）在2002年末/2003年初引发了全球疫情，并于2003/2004年冬季通过一次独立的动物传人传播导致了第二次疫情爆发。从第二次疫情爆发的首例患者中分离出的GD03毒株据报道可抵抗人单克隆抗体（hmAbs）80R和S3.1的中和作用，而这两种抗体能够有效中和首次疫情爆发时的病毒分离株。在此，我们报告两种hmAbs，即m396和S230.15，能够有效中和GD03以及首次SARS疫情爆发时的代表性分离株（Urbani、Tor2）和来自果子狸的分离株（SZ3、SZ16）。这些抗体还能保护受到Urbani或携带GD03和SZ16刺突（S）糖蛋白的重组病毒攻击的小鼠。两种抗体都与SARS-CoV受体ACE2竞争结合受体结合域（RBD），这表明一种涉及干扰SARS-CoV-ACE2相互作用的中和机制。在SARS-CoV刺突蛋白的RBD中鉴定出两个推定的热点残基（Ile-489和Tyr-491），它们可能构成了m396大部分的结合能量。Ile-489和Tyr-491残基在SARS-CoV刺突蛋白中高度保守，这表明了m396交叉反应性的一种可能机制。序列分析和诱变数据表明m396可能中和所有已知序列的人畜共患和流行的SARS-CoV分离株，但源自蝙蝠的毒株除外。这些抗体对两次SARS疫情爆发的分离株以及果子狸的分离株均表现出交叉反应性，并且在SARS-CoV感染的诊断、预防和治疗方面可能具有潜在应用价值。
