A Combination of Human Broadly Neutralizing Antibodies against Hepatitis B Virus HBsAg with Distinct Epitopes Suppresses Escape Mutations.
A Combination of Human Broadly Neutralizing Antibodies against Hepatitis B Virus HBsAg with Distinct Epitopes Suppresses Escape Mutations.
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人类广泛中和乙型肝炎病毒 HBsAg 的抗体与不同表位的组合可抑制逃逸突变
DOI：
10.1016/j.chom.2020.05.010
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发表时间：
2020-08-12
影响因子：
30.3
通讯作者：
Nussenzweig MC
中科院分区：
文献类型：
--
作者：
Wang Q;Michailidis E;Yu Y;Wang Z;Hurley AM;Oren DA;Mayer CT;Gazumyan A;Liu Z;Zhou Y;Schoofs T;Yao KH;Nieke JP;Wu J;Jiang Q;Zou C;Kabbani M;Quirk C;Oliveira T;Chhosphel K;Zhang Q;Schneider WM;Jahan C;Ying T;Horowitz J;Caskey M;Jankovic M;Robbiani DF;Wen Y;de Jong YP;Rice CM;Nussenzweig MC
尽管慢性乙型肝炎病毒 (HBV) 感染尚无有效治愈方法，但抗体具有保护作用，并构成感染恢复的临床相关因素。为了检查具有有效血清中和活性的个体对 HBV 的人类抗体反应，我们筛选了 144 名个体。选定的个体产生了广泛中和抗体 (bNAb) 的共享克隆，这些抗体针对 HBV S 抗原 (HBsAg) 上的 3 个非重叠表位。单一 bNAb 可保护人源化小鼠免受感染，但在已感染的小鼠中选择抗性突变。相比之下，感染是通过针对非重叠表位的 bNAb 组合来控制的，这些表位对人类感染期间常见的突变具有互补的敏感性。其中一种 bNAb 与肽表位的共晶显示出稳定的发夹环。这种结构包含临床免疫逃逸变体中经常突变的残基，为为什么 HBV 感染的免疫治疗可能需要互补 bNAb 的组合提供了分子解释。
Although there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and constitute clinical correlates of recovery from infection. To examine the human antibody response to HBV in individuals with potent serum neutralizing activity, we screened 144 individuals. The selected individuals produced shared clones of broadly neutralizing antibodies (bNAbs) that targeted 3 non-overlapping epitopes on the HBV S antigen (HBsAg). Single bNAbs protected humanized mice against infection, but selected for resistance mutations in mice with established infection. In contrast, infection was controlled by a combination of bNAbs targeting non-overlapping epitopes with complementary sensitivity to mutations that commonly emerge during human infection. Co-crystals of one of the bNAbs with a peptide epitope revealed a stabilized hairpin loop. This structure, which contains residues frequently mutated in clinical immune escape variants, provides a molecular explanation for why immunotherapy for HBV infection may require combinations of complementary bNAbs.
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影响因子：
32.4
作者：
Gilchuk P;Kuzmina N;Ilinykh PA;Huang K;Gunn BM;Bryan A;Davidson E;Doranz BJ;Turner HL;Fusco ML;Bramble MS;Hoff NA;Binshtein E;Kose N;Flyak AI;Flinko R;Orlandi C;Carnahan R;Parrish EH;Sevy AM;Bombardi RG;Singh PK;Mukadi P;Muyembe-Tamfum JJ;Ohi MD;Saphire EO;Lewis GK;Alter G;Ward AB;Rimoin AW;Bukreyev A;Crowe JE Jr
通讯作者：
Crowe JE Jr
影响因子：
12.7
作者：
Heijtink, RA;Kruining, J;Osterhaus, ADME
通讯作者：
Osterhaus, ADME
影响因子：
5.4
作者：
Abou-Jaoude, Georges;Sureau, Camille
通讯作者：
Sureau, Camille
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1073/pnas.93.5.1997
发表时间：
1996-03-05
影响因子：
11.1
作者：
Chen, YCJ;Delbrook, K;Mandecki, W
通讯作者：
Mandecki, W