In some immunocompromised patients with chronic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, considerable adaptive evolution occurs. Some substitutions found in chronic infections are lineage-defining mutations in variants of concern (VOCs), which has led to the hypothesis that VOCs emerged from chronic infections. In this study, we searched for drivers of VOC-like emergence by consolidating sequencing results from a set of 27 chronic infections. Most substitutions in this set reflected lineage-defining VOC mutations; however, a subset of mutations associated with successful global transmission was absent from chronic infections. We further tested the ability to associate antibody evasion mutations with patient-specific and virus-specific features and found that viral rebound is strongly correlated with the emergence of antibody evasion. We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody evasion in particular niches in a patient’s body. We suggest that a tradeoff exists between antibody evasion and transmissibility and that extensive monitoring of chronic infections is necessary to further understanding of VOC emergence.

在一些患有慢性严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染的免疫功能低下的患者中，会发生相当大的适应性进化。在慢性感染中发现的一些替代是关注变体 (VOC) 中的谱系定义突变，这导致了 VOC 来自慢性感染的假设。在这项研究中，我们通过整合一组 27 种慢性感染的测序结果来寻找类 VOC 出现的驱动因素。这组中的大多数替换反映了谱系定义的 VOC 突变；然而，与成功的全球传播相关的突变子集在慢性感染中不存在。我们进一步测试了将抗体逃避突变与患者特异性和病毒特异性特征相关联的能力，发现病毒反弹与抗体逃避的出现密切相关。我们在大多数患者中发现了动态多态性病毒种群的证据，这表明受损的免疫系统选择了患者体内特定壁龛中的抗体逃避。我们建议在抗体逃避和传播之间存在权衡，并且需要对慢性感染进行广泛监测以进一步了解 VOC 的出现。