Understanding the evolutionary mutational patterns of chronic SARS-CoV-2 infection

In a recent study posted to the medRxiv* preprint server, researchers elucidated the factors driving adaptive evolution in chronic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections.

Study: Drivers of adaptive evolution during chronic SARS-CoV-2 infections. Image Credit: CROCOTHERY/Shutterstock
Study: Drivers of adaptive evolution during chronic SARS-CoV-2 infections. Image Credit: CROCOTHERY/Shutterstock

Globally, more than 434 million COVID-19 infections have been recorded to date. There is a growing concern that the disease presents a chronic condition in some cases. Chronic SARS-CoV-2 illness is different and distinct from long COVID. In case of long COVID, COVID-19-associated symptoms persist even after recovery for weeks to months.

Usually, the clinical course of coronavirus disease 2019 (COVID-19) subsides within a few days with viral ribonucleic acid (RNA) shedding for a few days to weeks. In chronic COVID-19 infection, the replicative virus can be detected for an extended period. All known chronic (COVID-19) infections have been observed in patients with a severely immunocompromised state, such as individuals with acquired immunodeficiency syndrome (AIDS) and hematologic cancer, those undergoing immunosuppressive therapies, and organ transplant patients. In these people, virus clearance is hampered due to their immunological condition, and thereby the pathogen (SARS-CoV-2) thrives for an extended period.

It has been speculated that the SARS-CoV-2 variants might have evolved due to selective pressure created during chronic COVID-19. Moreover, it has been theorized that the selection of antibody-evasive mutations might occur in patients with chronic infection treated with monoclonal antibodies (mAbs) or convalescent plasma (CP).

The study

In the present study, researchers (re-)analyzed the evolutionary patterns seen in chronic COVID-19 infection from previously reported data and performed sequencing of six chronic COVID-19 patients at the Tel Aviv Sourasky Medical Center (TASMC).

The central objective of the study was to understand the conditions that drive adaptive evolution. Typically, chronic infection is described as showing both protracted viral shedding and the presence of the infectious virus. The authors included patients with high viral shedding for 20 days or more for whom SARS-CoV-2 whole-genome sequencing data were available.


The team identified 21 patients with the adopted criterion who were infected with SARS-CoV-2 lineages preceding the emergence of the Alpha variant. Additionally, six patients were detected in TASMC, with five suffering from hematological cancers and one with an autoimmune disorder. Four TASMC patients were diagnosed with pre-Alpha lineages and others with an Alpha lineage virus. All the 27 patients had immunosuppressive conditions due to any of the following disorders: anti-B cell treatment, AIDS, treatment with high steroid dose, and hematological cancer, among others.

The evolutionary patterns across the 27 patients were searched and compared with known patterns observed under 1) neutral evolution during the initial nine months of viral circulation and 2) the positive selection that led to the rise of mutants (five variants of concern or VOCs). The authors noted that most (65%) of the mutations were non-synonymous substitutions in the first nine months of viral circulation, which is expected given the absence of purifying and positive selective forces in the initial phase. The evolutionary patterns were mostly similar between chronic infections and VOCs, mainly under positive selection.

A three-amino acid deletion found in the nsp6 gene of four VOCs was not detected in any chronic set. Moreover, the S protein’s S1/S2 subunit interface showed an enrichment (driven mainly by P681H/R, a recurrent mutation) not observed in the chronic sets. Successful recurrent mutations were never observed in the chronic sets, but non-successful recurrent mutations were abundant, indicating a trade-off between transmissibility and antibody evasion.

Logistic regression analysis revealed that B cell-, steroid-, mAb-, and CP-treatments were insignificant predictors of antibody-evasion mutations. However, viral rebound after a drop in viral load was a significant predictor for evasive antibody mutations. These observations suggested that a weak immune response is the driver of adaptive evolution in the virus.


The researchers posit that partial penetration of antibodies to a particular niche (infected organ or within it) could lead to viral rebound coupled with antibody evasion. As such, viral clearance is prevented with an accompanying selection of antibody evasion mutations. No evidence was obtained to support the onward transmission of the virus from a chronically infected patient to the general public, possibly due to stringent isolation of immunosuppressed patients.

In summary, the study’s findings revealed that evolutionary mutational patterns of viruses from chronic infections are reminiscent of that in VOCs with a few exemptions. Viral rebound could be predictive of antibody evasion mutation, and therefore caution should be exercised upon such discoveries. However, viruses emerging in chronic COVID-19, in general, lack the potential for onward transmission. Still, more research is required to precisely forecast the emergence of variants causing chronic illness and identify mutations affecting transmissibility.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Tarun Sai Lomte

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.


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