Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike.
Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike.
复制标题
DOI：
10.1016/j.celrep.2021.108933
复制
发表时间：
2021-04-06
期刊：
影响因子：
8.8
通讯作者：
Sanders RW
中科院分区：
文献类型：
--
作者：
Derking R;Allen JD;Cottrell CA;Sliepen K;Seabright GE;Lee WH;Aldon Y;Rantalainen K;Antanasijevic A;Copps J;Yasmeen A;Cupo A;Cruz Portillo VM;Poniman M;Bol N;van der Woude P;de Taeye SW;van den Kerkhof TLGM;Klasse PJ;Ozorowski G;van Gils MJ;Moore JP;Ward AB;Crispin M;Sanders RW
当潜在的N-连接糖基化位点（PNGS）未被充分占据时，基于重组Env的疫苗上的人工聚糖孔发生，但在其病毒对应物上不发生。天然样SOSIP三聚体，包括临床候选物，在聚糖屏蔽中含有这样的孔，其诱导菌株特异性中和抗体（NAb）或非NAb。为了消除聚糖孔并模拟天然BG 505 Env的糖基化，我们用NxT替换BG 505 SOSIP上的所有12个NxS序列。除N133和N160外，所有PNGS几乎都已满员。通过将N133改变为NxS来增加N133位点的占据，而通过将附近的N156序列子恢复为NxS来恢复N160位点的占据。因此，非常接近的PNGS，例如N133-N137和N156-N160对，会影响彼此的占用。我们进一步应用这种方法来提高几种Env菌株的占有率。增加聚糖占有率应减少对疫苗抗原的脱靶免疫应答。Derking等人提出了一种增强重组HIV-1包膜三聚体上聚糖占据率以模拟病毒的策略。该策略消除了这些三聚体上诱导非中和抗体的人工聚糖孔。这些抗体的诱导可能会分散免疫聚焦策略。
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. Derking et al. present a strategy to enhance glycan occupancy on recombinant HIV-1 envelope trimers to mimic that of the virus. This strategy eliminates artificial glycan holes on these trimers that induce non-neutralizing antibodies. The induction of these antibodies could be distractive for immuno-focusing strategies.
登录
查看更多内容
影响因子：
8.8
作者：
Torrents de la Peña A;Julien JP;de Taeye SW;Garces F;Guttman M;Ozorowski G;Pritchard LK;Behrens AJ;Go EP;Burger JA;Schermer EE;Sliepen K;Ketas TJ;Pugach P;Yasmeen A;Cottrell CA;Torres JL;Vavourakis CD;van Gils MJ;LaBranche C;Montefiori DC;Desaire H;Crispin M;Klasse PJ;Lee KK;Moore JP;Ward AB;Wilson IA;Sanders RW
通讯作者：
Sanders RW
影响因子：
9.2
作者：
Brouwer PJM;Antanasijevic A;de Gast M;Allen JD;Bijl TPL;Yasmeen A;Ravichandran R;Burger JA;Ozorowski G;Torres JL;LaBranche C;Montefiori DC;Ringe RP;van Gils MJ;Moore JP;Klasse PJ;Crispin M;King NP;Ward AB;Sanders RW
通讯作者：
Sanders RW
影响因子：
16.6
作者：
Cao L;Pauthner M;Andrabi R;Rantalainen K;Berndsen Z;Diedrich JK;Menis S;Sok D;Bastidas R;Park SR;Delahunty CM;He L;Guenaga J;Wyatt RT;Schief WR;Ward AB;Yates JR 3rd;Burton DR;Paulson JC
通讯作者：
Paulson JC
影响因子：
64.5
作者：
de Taeye SW;Ozorowski G;Torrents de la Peña A;Guttman M;Julien JP;van den Kerkhof TL;Burger JA;Pritchard LK;Pugach P;Yasmeen A;Crampton J;Hu J;Bontjer I;Torres JL;Arendt H;DeStefano J;Koff WC;Schuitemaker H;Eggink D;Berkhout B;Dean H;LaBranche C;Crotty S;Crispin M;Montefiori DC;Klasse PJ;Lee KK;Moore JP;Wilson IA;Ward AB;Sanders RW
通讯作者：
Sanders RW
影响因子：
4.8
作者：
Eggink, Dirk;Langedijk, Johannes P. M.;Sanders, Rogier W.
通讯作者：
Sanders, Rogier W.