Persistent COVID-19 could drive virus evolution, new study suggests

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A study published in the journal Nature provides the prevalence of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at the population level and describes how persistent infection may contribute to viral evolution.

Study: Prevalence of persistent SARS-CoV-2 in a large community surveillance studyStudy: Prevalence of persistent SARS-CoV-2 in a large community surveillance study


Chronic persistent SARS-CoV-2 infection is considered to be the most likely contributor to the emergence of highly divergent viral variants with improved fitness. In particular, viral infection persists for months or even years in immunocompromised patients who are unable to clear the virus from the body because of a weakened immune system.

Over the course of chronic infection, SARS-CoV-2 gets exposed to the host’s immune system and other selective pressures that arise from long-term treatment. This can trigger the acquisition of new mutations in the viral genome, leading to the emergence of highly divergent viral variants that can potentially seed new outbreaks in the community.

In this study, scientists have estimated the prevalence of persistent SARS-CoV-2 infection in the general UK population and explored their contribution to long-COVID and their potential for adaptive viral evolution.

Study design

The scientists collected viral sequence data, symptoms, and epidemiological data from the Office for National Statistics COVID Infection Survey (ONS-CIS), a large-scale community-based surveillance study conducted in the UK.

They used the data to identify individuals with high-titer SARS-CoV-2 infections lasting for one month or more. They compared viral evolutionary changes, viral load, number of reported symptoms, and prevalence of long COVID (post-acute COVID-19 sequelae) between individuals with and without persistent SARS-CoV-2 infection.

Important observations

The scientists analyzed 93,927 high-quality SARS-CoV-2 sequences from the ONS-CIS data. The sequences were collected between November 2020 and August 2022 from 90,146 individuals living in 66,602 households across the UK.

The sequence analysis identified 381 persistent infections with high viral load (Ct value of 30 or lower) lasting for at least 26 days. These infections were caused by alpha, delta, BA.1, and BA.2 variants of SARS-CoV-2. Of all persistent infections, 54 lasted for at least 56 days. The most prolonged infection was with the BA.1 variant, which lasted for at least 193 days.

About 68% of the identified persistent infection samples showed no nucleotide differences at the consensus level during infection, indicating that sequences identified from persistent infections belong to the same infection.

The lack of consensus changes observed between several pairs of samples collected from the same infection indicated limited within-host adaptation (neutral evolution or weak selection). Further analysis of sequences with no consensus changes throughout infection indicated that the virus is probably replicating during infection despite acquiring no consensus changes.    

Despite significant evidence of weak position selection, the study identified 277 unique mutations and 18 unique deletions in persistently infected individuals. This observation indicates a period of strong positive selection. Many of these mutations have previously been identified as signature mutations in SARS-CoV-2 variants of concern, recurrent mutations in immunocompromised patients, or key mutations at target sites for monoclonal antibodies.  

The study identified two mutations (T1638I and T4311I) that emerged twice during persistent infections. These mutations were mildly deleterious based on the global phylogeny. As mentioned by the scientists, these mutations may be beneficial at the within-host level but deleterious at the between-host level, because mutations that are selected during persistent infection tend to be better at transmitting between individuals.

About 82% of identified persistent infection cases showed rebounding viral load dynamics, i.e., the resurgence in viral load after an initial drop during the course of infection. This finding highlights the presence of replicating viral populations in persistent infections.

Regarding clinical consequences, the study found that individuals with persistent infections remained mostly asymptomatic during the later stages of infection. Individuals with persistent infections showed a 55% higher probability of self-reporting long-COVID 12 weeks or more after infection than those with non-persistent infections.

Study significance

The study estimates that the prevalence of persistent SARS-CoV-2 infections that last for at least 60 days is approximately 0.1–0.5% in the general UK population. These infections can potentially give rise to new viral variants with divergent mutational landscapes.

Journal reference:
Dr. Sanchari Sinha Dutta

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.


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