A highly divergent SARS-CoV-2 lineage B.1.1 sample in a patient with long-term COVID-19

Abstract

We report the genomic analysis of a highly divergent SARS-CoV-2 sample obtained in October 2022 from an HIV+ patient with presumably long-term COVID-19 infection. Phylogenetic analysis indicates that the sample is characterized by a gain of 89 mutations since divergence from its nearest sequenced neighbor, which had been collected in September 2020 and belongs to the B.1.1 lineage, largely extinct in 2022. 33 of these mutations were coding and occurred in the Spike protein. Of these, 17 are lineage-defining in some of the variants of concern (VOCs) or are in sites where another mutation is lineage-defining in a variant of concern, and/or shown to be involved in antibody evasion, and/or detected in other cases of persistent COVID-19; these include some "usual suspects," such as Spike:L452R, E484Q, K417T, Y453F, and N460K. Molecular clock analysis indicates that mutations in this lineage accumulated at an increased rate compared to the ancestral B.1.1 strain. This increase is driven by the accumulation of nonsynonymous mutations, for an average dN/dS value of 2.2, indicating strong positive selection during within-patient evolution. Additionally, there is reason to believe that the virus had persisted for at least some time in the gastrointestinal tract, as evidenced by the presence of mutations that are rare in the general population samples but common in samples from wastewater. Our analysis adds to the growing body of research on evolution of SARS-CoV-2 in chronically infected patients and its relationship to the emergence of variants of concern.

Intrahost evolution leading to distinct lineages in the upper and lower respiratory tracts during SARS-CoV-2 prolonged infection

“…It is infrequent in sequenced genomes (0.1% in GISAID as of January 2024), yet computational analyses suggest a fitness advantage for the virus harbouring this change [24,28] . Unlike the previous amino acid changes, NSP3:K977Q has previously been observed in a VOC (Gamma, P.1) and has been detected in the context of chronic infections as well as within cryptic lineages sampled from wastewater [30][31][32] . This amino acid change enhances the activity of the SARS-CoV-2 papain-like protease, potentially modulating the host's innate immune response [33] .…”