英国剑桥大学Ravindra K. Gupta小组发现，慢性感染治疗过程中SARS-CoV-2可发生演化。该项研究成果于2021年2月5日在线发表在《自然》杂志上。

研究人员发现，慢性SARS-CoV-2，即在接受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，可在101天的23个时间点内产生全基因组超深序列 。在最初的57天中，接受了两个疗程的瑞德西韦后，总体病毒群体结构几乎未见变化。然而，在恢复性血浆疗法之后，研究人员观察到了明显的动态病毒群体转移，在S2中出现了带有D796H的主要病毒株，在突刺蛋白的S1 N端域NTD中出现了ΔH69/ΔV70。

由于被动转移的血清抗体减少，具有逃避基因型的病毒频率减少，然后在恢复血浆的最后一次失败治疗后重新恢复。在体外，携带ΔH69/ΔV70和D796H的突刺逃脱双突变体对恢复期血浆的敏感性适度降低，同时保持与野生型相似的感染性。D796H似乎是导致药敏性下降的主要因素，但引起了感染性缺陷。与野生型相比，ΔH69/ΔV70单个突变体的感染力高出两倍，可能弥补了D796H感染力的降低。

这些数据表明，在恢复期血浆治疗中，SARS-CoV-2会出现与观察到的病毒变异相关的强烈选择，并且能够降低对中和抗体的敏感性。 

据了解，SARS-CoV-2突刺蛋白对于病毒感染至关重要，并且是主要的抗体靶标。

附：英文原文

Title: SARS-CoV-2 evolution during treatment of chronic infection

Author: Steven A. Kemp, Dami A. Collier, Rawlings P. Datir, Isabella A. T. M. Ferreira, Salma Gayed, Aminu Jahun, Myra Hosmillo, Chloe Rees-Spear, Petra Mlcochova, Ines Ushiro Lumb, David J. Roberts, Anita Chandra, Nigel Temperton, Katherine Sharrocks, Elizabeth Blane, Yorgo Modis, Kendra Leigh, John Briggs, Marit van Gils, Kenneth G. C. Smith, John R. Bradley, Chris Smith, Rainer Doffinger, Lourdes Ceron-Gutierrez, Gabriela Barcenas-Morales, David D. Pollock, Richard A. Goldstein, Anna Smielewska, Jordan P. Skittrall, Theodore Gouliouris, Ian G. Goodfellow, Effrossyni Gkrania-Klotsas, Christopher J. R. Illingworth, Laura E. McCoy, Ravindra K. Gupta

Issue&Volume: 2021-02-05

Abstract: SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE21, 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.

DOI: 10.1038/s41586-021-03291-y

Source: https://www.nature.com/articles/s41586-021-03291-y