SARS-CoV-2 causes an acute respiratory tract infection that resolves in most people in less than a month. Yet some people with severely weakened immune systems fail to clear the virus, leading to persistent infections with high viral titres in the respiratory tract. In a subset of cases, persistent SARS-CoV-2 replication results in an accelerated accumulation of adaptive mutations that confer escape from neutralizing antibodies and enhance cellular infection. This may lead to the evolution of extensively mutated SARS-CoV-2 variants and introduce an element of chance into the timing of variant evolution, as variant formation may depend on evolution in a single person. Whether long COVID is also caused by persistence of replicating SARS-CoV-2 is controversial. One line of evidence is detection of SARS-CoV-2 RNA and proteins in different body compartments long after SARS-CoV-2 infection has cleared from the upper respiratory tract. However, thus far, no replication competent virus has been cultured from individuals with long COVID who are immunocompetent. In this Review, we consider mechanisms of viral persistence, intra-host evolution in persistent infections, the connection of persistent infections with SARS-CoV-2 variants and the possible role of SARS-CoV-2 persistence in long COVID. Understanding persistent infections may therefore resolve much of what is still unclear in COVID-19 pathophysiology, with possible implications for other emerging viruses.

SARS-CoV-2 会引起急性呼吸道感染，大多数人会在不到一个月的时间内消退。然而，一些免疫系统严重减弱的人无法清除病毒，导致呼吸道病毒滴度高的持续感染。在一部分病例中，持续的 SARS-CoV-2 复制导致适应性突变的加速积累，这些突变使中和抗体逃逸并增强细胞感染。这可能导致广泛突变的 SARS-CoV-2 变体的进化，并在变体进化的时间中引入偶然因素，因为变体的形成可能取决于单个人的进化。长期 COVID 是否也是由持续复制 SARS-CoV-2 引起的，这是有争议的。一条证据是，在 SARS-CoV-2 感染从上呼吸道清除很久后，可以在不同的身体隔室中检测到 SARS-CoV-2 RNA 和蛋白质。然而，到目前为止，尚未从具有免疫功能的长期 COVID 个体中培养出具有复制能力的病毒。在这篇综述中，我们考虑了病毒持续存在的机制、持续感染的宿主内进化、持续感染与 SARS-CoV-2 变体的联系以及 SARS-CoV-2 持续存在在长期 COVID 中的可能作用。因此，了解持续感染可能会解决 COVID-19 病理生理学中仍不清楚的大部分问题，并可能对其他新出现的病毒产生影响。