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增强可溶性 HIV-1 包膜三聚体的糖基占有,以模拟天然病毒刺突。

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

机构信息

Department of Medical Microbiology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.

School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK.

出版信息

Cell Rep. 2021 Apr 6;35(1):108933. doi: 10.1016/j.celrep.2021.108933.

Abstract

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.

摘要

在基于重组 Env 的疫苗中,当潜在的 N-连接糖基化位点(PNGS)未被占据时,就会出现人工聚糖孔,但在其对应的病毒中不会出现这种情况。类似天然 SOSIP 的三聚体,包括临床候选物,在聚糖屏蔽中都存在这种孔,可诱导针对特定毒株的中和抗体(NAb)或非中和抗体。为了消除聚糖孔并模拟天然 BG505 Env 的糖基化,我们用 NxT 替换了 BG505 SOSIP 上所有 12 个 NxS 序列。除了 N133 和 N160 之外,所有 PNGS 几乎都被完全占据。通过将 N133 替换为 NxS,可以增加 N133 位点的占据,而通过将附近的 N156 序列恢复为 NxS,可以恢复 N160 位点的占据。因此,彼此靠近的 PNGS,如 N133-N137 和 N156-N160 对,会影响彼此的占据。我们进一步应用这种方法来提高几种Env 株的占据度。增加聚糖占据度应该会减少疫苗抗原的非靶向免疫反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2601/8804554/62d394c20312/nihms-1768927-f0001.jpg

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