SARS-CoV-2 intra-host evolution during prolonged infection in an immunocompromised patient

Quaranta, Erika; Fusaro, Alice; Giussani, Edoardo; D’Amico, Valeria; Varotto, Maria; Pagliari, Matteo; Giordani, Maria Teresa; Zoppelletto, Maira; Merola, Francesca Reduzzi; Antico, Antonio; Stefanelli, Paola; Terregino, Calogero; Monne, Isabella

doi:10.1016/j.ijid.2022.06.023

Cited by 27 publications

(26 citation statements)

References 21 publications

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“…High DVG Jfreq was observed in one COVID-19 persistent patient. SARS-CoV-2 can develop persistent infections in immunosuppressive patients (Caccuri, Messali et al 2022, Quaranta, Fusaro et al 2022, and DVGs have been reported to facilitate viral persistence (Sun and López 2017). To examine whether DVGs are associated with persistent SARS-CoV-2 infection in patient, we identified one NGS dataset, where nasal samples were taken at 9 time points from one immunosuppressive patient who was infected with SARS-CoV-2 and was positive for virus up to 140 days since the first hospital admission (PRJEB47786).…”

Section: Figure 6 Dvg+ Cells Expressed Primary Ifns Earlier Than Dvg-...mentioning

confidence: 99%

Generation and functional analysis of defective viral genomes during SARS-CoV-2 infection

Zhou

Gilliam

et al. 2022

Preprint

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Defective viral genomes (DVGs) have been identified in many RNA viruses as a major factor influencing antiviral immune response and viral pathogenesis. However, the generation and function of DVGs in SARS-CoV-2 infection are less known. In this study, we elucidated DVG generation in SARS-CoV-2 and its relationship with host antiviral immune response. We observed DVGs ubiquitously from RNA-seq datasets of in vitro infections and autopsy lung tissues of COVID-19 patients. Four genomic hotspots were identified for DVG recombination and RNA secondary structures were suggested to mediate DVG formation. Functionally, bulk and single cell RNA-seq analysis indicated the IFN stimulation of SARS-CoV-2 DVGs. We further applied our criteria to the NGS dataset from a published cohort study and observed significantly higher DVG amount and frequency in symptomatic patients than that in asymptomatic patients. Finally, we observed unusually high DVG frequency in one immunosuppressive patient up to 140 days after admitted to hospital due to COVID-19, first-time suggesting an association between DVGs and persistent viral infections in SARS-CoV-2. Together, our findings strongly suggest a critical role of DVGs in modulating host IFN responses and symptom development, calling for further inquiry into the mechanisms of DVG generation and how DVGs modulate host responses and infection outcome during SARS-CoV-2 infection.

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Section: Figure 6 Dvg+ Cells Expressed Primary Ifns Earlier Than Dvg-...mentioning

confidence: 99%

Generation and functional analysis of defective viral genomes during SARS-CoV-2 infection

Zhou

Gilliam

et al. 2022

Preprint

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“…This conclusion is supported by another recent case study with an immunocompromised patient, which also found multiple mutations on S:484. 11 As is the case for other viruses, our results suggest that combination strategies accelerating viral clearance may be required to clear viral populations with pre-existing mutations within vulnerable patients.…”

Section: Discussionmentioning

confidence: 60%

“…These datasets can give us insight into evolutionary events that are not observed in acute infections, such as an instance of recombination between two viral strains 10 or the presence of distinct viral populations with immune escaping mutations in a single sample. 11 Here, we describe the genetic events that arose in two patients with hematologic cancers that were infected by SARS-CoV-2 for several months. Samples from the first patient (Q1) were collected by the Public Health Laboratory of Québec (LSPQ), in Canada.…”

Section: Introductionmentioning

confidence: 99%

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Intra-host viral populations of SARS-CoV-2 in immunosuppressed patients with hematologic cancers

Fournelle

Mostefai

Brunet-Ratnasingham

et al. 2022

Preprint

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Throughout the SARS-CoV-2 pandemic, several variants of concern (VOC) have been identified, many of which share recurrent mutations in the spike protein's receptor binding domain (RBD). This region coincides with known epitopes and can therefore have an impact on immune escape. Protracted infections in immunosuppressed patients have been hypothesized to lead to an enrichment of such mutations and therefore drive evolution towards VOCs. Here, we show that immunosuppressed patients with hematologic cancers develop distinct populations with immune escape mutations throughout the course of their infection. Notably, by investigating the co-occurrence of substitutions on individual sequencing reads in the RBD, we found quasispecies harboring mutations that confer resistance to known monoclonal antibodies (mAbs) such as S:E484K and S:E484A. Furthermore, we provide the first evidence for a viral reservoir based on intra-host phylogenetics. Our results on viral reservoirs can shed light on protracted infections interspersed with periods where the virus is undetectable as well as an alternative explanation for some long-COVID cases. Our findings also highlight that protracted infections should be treated with combination therapies rather than by a single mAbs to clear pre-existing resistant mutations.

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“…Although there are many other causes for variant emergence (host jump or adaptation, vaccine exposure, to name the most frequent), data confirm that immunocompromised patients with long-term SARS-CoV-2 replication are particularly susceptible to resistance and transmissible variant emergence (Clark et al, 2021;Destras et al, 2022;Quaranta et al, 2022;Sabin et al, 2022). The emergence of resistance mutation thus impacting treatment efficacy is more likely if a patient has been exposed to specific antiviral drugs.…”

Section: Protecting Emerging Treatment Optionsmentioning

confidence: 99%

Rethinking treatment paradigms for the deployment of SARS-CoV-2 antiviral drugs on the shifting landscape of new variants

et al. 2022

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SARS-CoV-2 intra-host evolution during prolonged infection in an immunocompromised patient

Cited by 27 publications

References 21 publications

Generation and functional analysis of defective viral genomes during SARS-CoV-2 infection

Generation and functional analysis of defective viral genomes during SARS-CoV-2 infection

Intra-host viral populations of SARS-CoV-2 in immunosuppressed patients with hematologic cancers

Rethinking treatment paradigms for the deployment of SARS-CoV-2 antiviral drugs on the shifting landscape of new variants

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