Structural basis for potent antibody-mediated neutralization of human cytomegalovirus

被引:68
|
作者
Chandramouli, Sumana [1 ]
Malito, Enrico [1 ]
TuongVi Nguyen [1 ,3 ]
Luisi, Kate [1 ]
Donnarumma, Danilo [2 ]
Xing, Yi [1 ,4 ]
Norais, Nathalie [2 ]
Yu, Dong [1 ]
Carfi, Andrea [1 ,5 ]
机构
[1] GSK Vaccines, 14200 Shady Grove Rd, Rockville, MD 20850 USA
[2] GSK Vaccines, Via Fiorentina 1, I-53100 Siena, Italy
[3] H3 Biomed, 300 Technol Sq, Cambridge, MA 02139 USA
[4] Broad Inst, 415 Main St, Cambridge, MA 02142 USA
[5] Valera LLC, 500 Technol Sq, Cambridge, MA 02139 USA
关键词
CRYSTAL-STRUCTURE; UL131-128; GENES; COMPLEX; VIRUS; VACCINE; GH/GL; INFECTION; DESIGN; SYSTEM; CELLS;
D O I
10.1126/sciimmunol.aan1457
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Human cytomegalovirus (HCMV) is the leading viral cause of birth defects and organ transplant rejection. The HCMV gH/gL/UL128/UL130/UL131A complex (Pentamer) is the main target of humoral responses and thus a key vaccine candidate. We report two structures of Pentamer bound to human neutralizing antibodies, 8121 and 916, at 3.0 and 5.9 angstrom resolution, respectively. The HCMV gH/gL architecture is similar to that of Epstein-Barr virus (EBV) except for amino-terminal extensions on both subunits. The extension of gL forms a subdomain composed of a three-helix bundle and a beta hairpin that acts as a docking site for UL128/UL130/UL131A. Structural analysis reveals that Pentamer is a flexible molecule, and suggests sites for engineering stabilizing mutations. We also identify immunogenic surfaces important for cellular interactions by epitope mapping and functional assays. These results can guide the development of effective vaccines and immunotherapeutics against HCMV.
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页数:10
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