A longitudinal study of SARS-CoV-2 evolution and molecular characterisation of variants in immunocompromised individuals with persistent infection

概述有些人由于某些治疗，药物或疾病而免疫系统减弱。免疫系统减弱会使抵抗病毒引起的感染变得更加困难，这意味着感染可能会持续很长时间。我们发现，一些人可以持续感染导致COVID-19（也称为SARS-CoV-2）的病毒数月。当病毒在我们体内繁殖时，它会发生变异，这就是病毒遗传密码发生变化的地方。这些突变导致病毒的“变种”。病毒的某些变体可能更容易传播，导致更严重的疾病，或使治疗和疫苗接种效果降低。免疫系统较弱的个体的持续感染可能会使其体内出现变异，因为病毒会继续繁殖，而且他们较弱的免疫系统无法在出现新变异时杀死它们。随着病毒产生新的变种，我们可以研究每个连续突变如何改变病毒的特性。具体来说，这项研究将研究突变如何改变病毒与我们免疫系统部分相互作用的方式。基因组测序，以确定在持续感染过程中出现的变异。我们将使用基因组测序来确定在持续感染过程中出现的突变，特别是寻找已知使病毒更容易传播或更致命的变异。使用深度基因组测序，我们将研究持续感染个体中存在的不同变异，即使是那些在感染个体中仅以低水平存在的变异。这项技术将使我们能够了解随着时间的推移以及对COVID-19的不同治疗或影响免疫系统的其他疾病的药物的反应，出现哪些变种。病毒变种的实验室实验。我们可以从患者的样本中培养病毒在实验室中研究不同变种在实验中的表现。这将包括实验，以了解变体如何逃脱免疫系统的控制，从而更好地了解不同变体的特性以及变体如何与我们的身体相互作用。我们将使用从持续感染个体中纵向收集的样本来观察每个新突变如何改变变体的特性，从而让我们深入了解病毒如何与我们的细胞和免疫系统相互作用。首先，我们将研究持续感染期间出现的突变是否会降低抗体对病毒的免疫能力。这将使用来自持续感染个体的抗体，来自从病毒中恢复的其他人的抗体，以及疫苗接种产生的抗体。第二，我们将观察在持续感染的个体中随着时间的推移发生的变异是否会增加病毒对限制感染的细胞（称为干扰素）中免疫反应的抵抗力。通过使用来自相同个体但在不同时间点出现新突变的病毒，我们将能够研究哪些变体赋予逃避这些免疫反应的能力。未来几个月可能会有更多的COVID-19治疗方法，例如抗体疗法。随着时间的推移，我们将能够看到这些治疗是否会导致新的变异产生。科学家和临床医生进行这项研究。这项研究将由伦敦国王学院、盖伊和圣托马斯NHS基金会信托基金、和伦敦大学学院。总结我们的目标是了解如何变异的病毒，导致新冠肺炎-19通过调查持续感染的个体中的病毒来开发。我们将研究这些个体中产生了哪些变异，然后在实验室中培养这些变异，以研究突变如何影响免疫反应。

OverviewSome people have a weakened immune system due to certain treatments, medicines or illnesses. A weakened immune system can make it more difficult to fight infections caused by viruses, meaning infections can persist for a long time. We have found some individuals can become persistently infected for many months with the virus that causes COVID-19 (also known as SARS-CoV-2). As the virus reproduces in our bodies it can mutate, which is where changes occur in the genetic code of the virus. These mutations cause 'variants' of the virus. Some variants of the virus may spread more easily, cause more severe disease, or make treatments and vaccination less effective. Persistent infection in individuals with a weakened immune system may allow variants to arise in their body, as the virus continues to reproduce and because their weakened immune system cannot kill new variants as they arise. As the virus develops new variants we can investigate how each sequential mutation changes the properties of the virus. Specifically this research will investigate how mutations change how the virus interacts with parts of our immune system. Genome sequencing to identify variants arising during persistent infection.We will use genome sequencing to identify the mutations that arise during persistent infection, especially looking for variants that are known to make the virus spread more easily or more deadly. Using deep genome sequencing we will look at the different variants that exist in persistently infected individuals, even those variants that exist only at low levels in the infected individual. This technique will allow us to see which variants arise over time and in response to different treatments for COVID-19 or medicines for other conditions affecting their immune system.Laboratory experiments with variants of the virus.From the patients' samples we can grow the virus in the laboratory to investigate how different variants behave in experiments. This will include experiments to see how variants escape control of the immune system, allowing a better understanding of the properties of different variants and how the variants interact with our bodies. We will use samples collected longitudinally from persistently infected individuals to see how each new mutation changes the properties of the variants, giving us insight into how the virus interacts with our cells and immune system. First we will investigate if mutations that arise during persistent infection decrease the ability of antibodies to inactivate the virus. This will use antibodies from the persistently infected individual, from others who recover from the virus, and from antibodies produced by vaccination. Second, we will see if variants that occur over time in persistently infected individuals increase resistance of the virus to immune responses in cells that limit infection, called interferon. By using virus from the same individuals but at different timepoints when there are new mutations it will allow us to investigate which variants confer the ability to escape these immune responses.More treatments for COVID-19 may become available in the coming months, such as antibody therapies. By following individuals over time we will be able to see if these treatments lead to new variants being produced.Scientists and clinicians carrying out this research.The research will be conducted by clinicians and scientists working at King's College London, Guy's and St. Thomas NHS Foundation Trust, and University College London.SummaryWe aim to understand how variants of the virus that causes COVID-19 develop by investigating the virus in individuals persistently infected. We will investigate which variants develop in these individuals, and then grow these variants in the laboratory to study how mutations affect immune responses.