Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses.
Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses.
复制标题
DOI：
10.1126/scitranslmed.abl5399
复制
发表时间：
2022-03-16
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
啮齿动物传播的汉坦病毒普玛拉病毒（PUUV）和相关病原体引起人类肾综合征出血热（HFRS）。其他汉坦病毒，包括安第斯病毒（ANDV）和Sin Nombre病毒，引起一种独特的人畜共患疾病，汉坦病毒心肺综合征（HCPS）。尽管这些感染很严重，而且病死率很高，但目前还没有获得fda批准的汉坦病毒对策。最近的研究表明，单克隆抗体可能具有治疗作用。我们在此描述了从puuv经验丰富的供体中分离出抗四聚体Gn/Gc糖蛋白尖峰的人类中和单克隆抗体（nab）。我们定义了一类优势的nab，识别Gn的“封盖环”，掩盖Gc中的疏水融合环。这类nab的一个子集，包括ADI-42898，结合了Gn/Gc复合物，但不单独结合Gn，这强烈表明它们识别包含Gn和Gc的四元表位。ADI-42898阻断了7种HCPS和hfrs相关汉坦病毒的细胞进入，单次剂量该nAb可以分别保护叙利亚仓鼠和银行田鼠，它们分别受到高毒力HCPS-致病性ANDV和hfrs -致病性puv的攻击。ADI-42898作为抗HCPS和HFRS的候选药物具有广阔的临床开发前景，其Gn/Gc识别模式为开发具有广泛保护性的汉坦病毒疫苗提供了参考。识别病毒糖蛋白复合物的人中和抗体对正汉坦病毒具有广泛的保护作用。
The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have significant case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing monoclonal antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the ‘capping loop’ of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked cell entry of seven HCPS- and HFRS-associated hantaviruses and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines. Human neutralizing antibodies recognizing the viral glycoprotein complex are broadly protective against orthohantaviruses.
登录
查看更多内容
影响因子：
5.8
作者：
Kerkman PF;Dernstedt A;Tadala L;Mittler E;Dannborg M;Sundling C;Maleki KT;Tauriainen J;Tuiskunen-Bäck A;Wigren Byström J;Ocaya P;Thunberg T;Jangra RK;Román-Sosa G;Guardado-Calvo P;Rey FA;Klingström J;Chandran K;Puhar A;Ahlm C;Forsell MN
通讯作者：
Forsell MN
影响因子：
--
作者：
Golden JW;Hammerbeck CD;Mucker EM;Brocato RL
通讯作者：
Brocato RL
影响因子：
6.4
作者：
Duehr, James;McMahon, Meagan;Krammer, Florian
通讯作者：
Krammer, Florian
影响因子：
5.4
作者：
Huiskonen, Juha T.;Hepojoki, Jussi;Gruenewald, Kay
通讯作者：
Gruenewald, Kay
影响因子：
5.9
作者：
Guardado-Calvo, Pablo;Rey, Felix A.
通讯作者：
Rey, Felix A.