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  • Review Article
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The consequences of SARS-CoV-2 within-host persistence

Nature Reviews Microbiology volume 23, pages 288–302 (2025)Cite this article

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Abstract

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.

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Fig. 1: Mechanisms of SARS-CoV-2 persistence.
Fig. 2: Evolution in persistent infection avoids the transmission bottleneck.
Fig. 3: Convergence of selective pressure between viruses evolved in persistent infections and SARS-CoV-2 variants.
Fig. 4: Regions where extensively mutated variants were detected.

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Acknowledgements

This study was supported by Bill and Melinda Gates INV-018944, Wellcome Trust 226137/Z/22/Z and South African Medical Research Council awards to A.S. The authors thank G. Lustig for advice and help with the figures.

Author information

Authors and Affiliations

  1. The Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Alex Sigal

  2. Africa Health Research Institute, Durban, South Africa

    Alex Sigal

  3. School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa

    Alex Sigal

  4. Biozentrum, University of Basel, Basel, Switzerland

    Richard A. Neher

  5. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    Richard A. Neher

  6. KwaZulu-Natal Research Innovation & Sequencing Platform, School of Laboratory Medicine & Medical Sciences, University of KwaZulu-Natal, Durban, South Africa

    Richard J. Lessells

  7. Centre for the AIDS Programme of Research in South Africa, Durban, South Africa

    Richard J. Lessells

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  1. Alex Sigal
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  2. Richard A. Neher
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  3. Richard J. Lessells
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Alex Sigal.

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Competing interests

A.S. has received an honorarium from Pfizer for consultation and has active grants on COVID-19 from the Bill and Melinda Gates Foundation and The Wellcome Trust. R.A.N is a paid consultant for Moderna and BioNtech, and has active grants on COVID-19 from the Swiss National Science Foundation and the Swiss Federal Office for Public Health. R.J.L declares no competing interests.

Peer review

Peer review information

Nature Reviews Microbiology thanks Stanley Perlman; Malik Peiris, who co-reviewed with Ray T. Y. So; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Sigal, A., Neher, R.A. & Lessells, R.J. The consequences of SARS-CoV-2 within-host persistence. Nat Rev Microbiol 23, 288–302 (2025). https://doi.org/10.1038/s41579-024-01125-y

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