TY - JOUR TI - An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein AU - Flyak, Andrew I AU - Ruiz, Stormy E AU - Salas, Jordan AU - Rho, Semi AU - Bailey, Justin R AU - Bjorkman, Pamela J A2 - Ojala, Päivi M A2 - Li, Wenhui A2 - Zhou, Tongqing A2 - Houghton, Michael VL - 9 PY - 2020 DA - 2020/03/03 SP - e53169 C1 - eLife 2020;9:e53169 DO - 10.7554/eLife.53169 UR - https://doi.org/10.7554/eLife.53169 AB - A vaccine protective against diverse HCV variants is needed to control the HCV epidemic. Structures of E2 complexes with front layer-specific broadly neutralizing antibodies (bNAbs) isolated from HCV-infected individuals, revealed a disulfide bond-containing CDRH3 that adopts straight (individuals who clear infection) or bent (individuals with chronic infection) conformation. To investigate whether a straight versus bent disulfide bond-containing CDRH3 is specific to particular HCV-infected individuals, we solved a crystal structure of the HCV E2 ectodomain in complex with AR3X, a bNAb with an unusually long CDRH2 that was isolated from the chronically-infected individual from whom the bent CDRH3 bNAbs were derived. The structure revealed that AR3X utilizes both its ultralong CDRH2 and a disulfide motif-containing straight CDRH3 to recognize the E2 front layer. These results demonstrate that both the straight and bent CDRH3 classes of HCV bNAb can be elicited in a single individual, revealing a structural plasticity of VH1-69-derived bNAbs. KW - Hepatitis C virus KW - broadly neutralizing antibodies KW - immunogen design JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -