SARS-CoV-2 evolution during treatment of chronic infection.
SARS-CoV-2 evolution during treatment of chronic infection.
复制标题
DOI：
10.1038/s41586-021-03291-y
复制
发表时间：
2021-04
期刊：
影响因子：
64.8
通讯作者：
Gupta RK
中科院分区：
文献类型：
--
作者：
Kemp SA;Collier DA;Datir RP;Ferreira IATM;Gayed S;Jahun A;Hosmillo M;Rees-Spear C;Mlcochova P;Lumb IU;Roberts DJ;Chandra A;Temperton N;CITIID-NIHR BioResource COVID-19 Collaboration;COVID-19 Genomics UK (COG-UK) Consortium;Sharrocks K;Blane E;Modis Y;Leigh KE;Briggs JAG;van Gils MJ;Smith KGC;Bradley JR;Smith C;Doffinger R;Ceron-Gutierrez L;Barcenas-Morales G;Pollock DD;Goldstein RA;Smielewska A;Skittrall JP;Gouliouris T;Goodfellow IG;Gkrania-Klotsas E;Illingworth CJR;McCoy LE;Gupta RK
SARS-CoV-2刺突蛋白通过与ACE 2的结合对病毒感染至关重要，并且是主要的抗体靶标。在这里，我们报告了慢性SARS-CoV-2，在用恢复期血浆治疗的免疫抑制个体中，对中和抗体的敏感性降低，在跨越101天的23个时间点产生全基因组超深序列。在前57天的两个疗程的remdesivir后，观察到总体病毒群体结构几乎没有变化。然而，在恢复期血浆治疗后，我们观察到大的动态病毒群体变化，出现了在S2中携带D 796 H和在刺突蛋白的S1 N-末端结构域NTD中携带ΔH69/ΔV70的优势病毒株。随着被动转移的血清抗体减少，逃逸基因型的病毒频率减少，然后在恢复期血浆的最后一个不成功的过程中返回。在体外，携带ΔH69/ΔV70和D 796 H的刺突逃逸双突变体赋予对恢复期血浆的适度降低的敏感性，同时保持与野生型相似的感染性。D 796 H似乎是降低敏感性的主要因素，但引起了感染性缺陷。ΔH69/ΔV70单突变体的感染性是野生型的两倍，可能弥补了D 796 H的感染性降低。这些数据揭示了在恢复期血浆治疗期间对SARS-CoV-2的强选择性，与病毒变体的出现相关，并有证据表明对中和抗体的敏感性降低。
SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.
登录
查看更多内容
影响因子：
10.7
作者：
Minh BQ;Nguyen MA;von Haeseler A
通讯作者：
von Haeseler A
影响因子：
6.4
作者：
Gregson, J.;Rhee, S. Y.;Gupta, R. K.
通讯作者：
Gupta, R. K.
影响因子：
5.3
作者：
Martin DP;Murrell B;Golden M;Khoosal A;Muhire B
通讯作者：
Muhire B
DOI：
10.1073/pnas.0802203105
发表时间：
2008-05-27
影响因子：
11.1
作者：
Keele, Brandon F.;Giorgi, Elena E.;Shaw, George M.
通讯作者：
Shaw, George M.
影响因子：
10.7
作者：
Katoh K;Standley DM
通讯作者：
Standley DM