Publication date: Jul 11, 2025

People who are immunocompromised can develop persistent SARS-CoV-2 infections. Several viral mutations accumulated during the course of such persistent infections have also been observed in prominent variants of concern (VOCs). Here, we characterise persistent infection and viral evolution of SARS-CoV-2 lasting more than 750 days in a person with advanced HIV-1 infection. Between March, 2021, and July, 2022, eight clinical specimens were collected from a person living with HIV, neither receiving antiretroviral therapy nor virally suppressed, and presumed to have been initially infected with SARS-CoV-2 in mid-May, 2020. Viral RNA was extracted from each swab and an amplicon-based sequencing approach was used for genomic analysis of SARS-CoV-2. Variable sites were characterised at the consensus and subconsensus levels, and phylogenetic tools were applied to analyse viral evolution. Publicly available SARS-CoV-2 sequences from GenBank were leveraged to contextualise our sequenced samples and identify any potential evidence of transmission. Genomes formed a monophyletic cluster in the B. 1 lineage. 68 consensus and 67 subconsensus single nucleotide variants were observed over the course of infection. The intrahost clock rate remained similar to that of the interhost rate in contemporaneous community sequences (6.74 cD7 10 [95% credible interval 5.05 cD7 10 to 8.54 cD7 10] substitutions per site per year vs 6.11 cD7 10 [5.54 cD7 10 to 6.66 cD7 10]). Mutations grouped into two distinct subpopulations present throughout infection. 10 non-synonymous mutations in the spike protein gene were at positions in common with those defining the omicron lineage (BA. 1 or BA. 2), of which nine were present before November, 2021. Nine of 18 substitutions present throughout infection were rare in online databases, suggesting a lack of long transmission chains descending from this individual. Convergent SARS-CoV-2 evolution, both in and outside the spike protein, observed in this study suggests parallels with the evolutionary process leading to emergence of the omicron VOC. The inferred absence of onward infections might indicate a loss of transmissibility during adaptation to a single host. Our results underscore the importance of appropriate treatment to cure persistent SARS-CoV-2 infections and monitoring them to understand how mutations contribute to viral adaptation. National Institute of General Medical Sciences of the National Institutes of Health, Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, MassCPR, and Morris Singer Foundation.

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Semantics

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