Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
Cell Host Microbe. 2020 Aug 12;28(2):335-349.e6. doi: 10.1016/j.chom.2020.05.010. Epub 2020 Jun 5.
Although there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and correlate with recovery from infection. To examine the human antibody response to HBV, we screened 124 vaccinated and 20 infected, spontaneously recovered 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 prior 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. The co-crystal structure of one of the bNAbs with an HBsAg 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.
尽管目前尚无有效治疗慢性乙型肝炎病毒（HBV）感染的方法，但抗体具有保护作用，并与感染的恢复相关。为了研究人体对 HBV 的抗体反应，我们筛选了 124 名接种疫苗和 20 名自然恢复的感染者。选定的个体产生了广泛中和抗体（bNAbs）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 bNAbs 可保护人源化小鼠免受感染，但在先前已建立感染的小鼠中选择了耐药突变。相比之下，通过针对非重叠表位的 bNAbs 组合来控制感染，这些 bNAbs 对在人类感染过程中经常出现的突变具有互补的敏感性。一种 bNAbs 与 HBsAg 肽表位的共结晶结构揭示了一个稳定的发夹环。该结构包含在临床免疫逃逸变体中经常发生突变的残基，为为什么 HBV 感染的免疫疗法可能需要互补的 bNAbs 组合提供了分子解释。
