Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike

被引：32

作者：

Derking, Ronald ^{[1
]}

Allen, Joel D. ^{[2
]}

Cottrell, Christopher A. ^{[3
]}

Sliepen, Kwinten ^{[1
]}

Seabright, Gemma E. ^{[2
,4
]}

Lee, Wen-Hsin ^{[3
]}

Aldon, Yoann ^{[1
]}

Rantalainen, Kimmo ^{[3
]}

Antanasijevic, Aleksandar ^{[3
]}

Copps, Jeffrey ^{[3
]}

Yasmeen, Anila ^{[5
]}

Cupo, Albert ^{[5
]}

Portillo, Victor M. Cruz ^{[5
]}

Poniman, Meliawati ^{[1
]}

Bol, Niki ^{[1
]}

van Der Woude, Patricia ^{[1
]}

de Taeye, Steven W. ^{[1
]}

van den Kerkhof, Tom L. G. M. ^{[1
]}

Klasse, P. J. ^{[5
]}

Ozorowski, Gabriel ^{[3
,6
,7
]}

van Gils, Marit J. ^{[1
]}

Moore, John P. ^{[5
]}

Ward, Andrew B. ^{[3
,6
,7
]}

Crispin, Max ^{[2
]}

Sanders, Rogier W. ^{[1
,5
]}

机构：

[1] Univ Amsterdam, Amsterdam Infect & Immun Inst, Dept Med Microbiol, Amsterdam UMC, NL-1105 AZ Amsterdam, Netherlands

[2] Univ Southampton, Sch Biol Sci, Southampton SO17 1BJ, Hants, England

[3] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA USA

[4] Univ Oxford, Oxford Glycobiol Inst, Dept Biochem, Oxford OX1 3QU, England

[5] Cornell Univ, Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA

[6] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, Ctr HIV AIDS Vaccine Dev, La Jolla, CA 92037 USA

[7] Scripps Res Inst, Collaborat Aids Vaccine Discovery CAVD, La Jolla, CA 92037 USA

来源：

CELL REPORTS | 2021年 / 35卷 / 01期

基金：

欧盟地平线“2020”;

关键词：

IMMUNODEFICIENCY-VIRUS TYPE-1; CRYO-EM STRUCTURE; N-GLYCOSYLATION; CONFORMATIONAL EPITOPE; BROAD NEUTRALIZATION; ANTIBODY-RESPONSES; ENV; GLYCOPROTEIN; RECOMBINANT; SOSIP.664;

D O I：

10.1016/j.celrep.2021.108933

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Artificial glycan holes on recombinant Env-based vaccines occur when a potential N-linked glycosylation site (PNGS) is under-occupied, but not on their viral counterparts. Native-like SOSIP trimers, including clinical candidates, contain such holes in the glycan shield that induce strain-specific neutralizing antibodies (NAbs) or non-NAbs. To eliminate glycan holes and mimic the glycosylation of native BG505 Env, we replace all 12 NxS sequons on BG505 SOSIP with NxT. All PNGS, except N133 and N160, are nearly fully occupied. Occupancy of the N133 site is increased by changing N133 to NxS, whereas occupancy of the N160 site is restored by reverting the nearby N156 sequon to NxS. Hence, PNGS in close proximity, such as in the N133-N137 and N156-N160 pairs, affect each other's occupancy. We further apply this approach to improve the occupancy of several Env strains. Increasing glycan occupancy should reduce off-target immune responses to vaccine antigens.

引用

页数：21

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