Viral Population Heterogeneity and Fluctuating Mutational Pattern during a Persistent SARS-CoV-2 Infection in an Immunocompromised Patient (original) (raw)
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Biomedicines
A successful Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant, B.1.1.7, has recently been reported in the UK, causing global alarm. Most likely, the new variant emerged in a persistently infected patient, justifying a special focus on these cases. Our aim in this study was to explore certain clinical profiles involving severe immunosuppression that may help explain the prolonged persistence of viable viruses. We present three severely immunosuppressed cases (A, B, and C) with a history of lymphoma and prolonged SARS-CoV-2 shedding (2, 4, and 6 months), two of whom finally died. Whole-genome sequencing of 9 and 10 specimens from Cases A and B revealed extensive within-patient acquisition of diversity, 12 and 28 new single nucleotide polymorphisms, respectively, which suggests ongoing SARS-CoV-2 replication. This diversity was not observed for Case C after analysing 5 sequential nasopharyngeal specimens and one plasma specimen, and was only observed in one bronchoa...
Frontiers in Virology
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic, threatening global public health. Several cases of persistent infection have been described, but there are few reports that compared the genetic variability among samples collected from the patient during infection. In the current study, we reported a viral genetic analysis of a diabetic male patient with Non-Hodgkin Lymphoma affected by persistent SARS-CoV-2 infection. We sequenced the patient-derived viral isolated both from oro/nasopharyngeal swab and VeroE6 cell line, collected from the same patient at different points of the infection. Due to the insufficient material of the second swab received, in order to obtain a complete coverage of the viral genome, it was convenient to perform a virus isolation after cell culture. Both genomes belonged to Pangolin Lineage B.1, Nextstrain clade 20A and GISAID clade G. The mutation spectrum predicted for the two viral genomes reveal three additionally m...
SARS-CoV-2 quasi-species analysis from patients with persistent nasopharyngeal shedding
Scientific Reports
At the time of a new and unprecedented viral pandemic, many questions are being asked about the genomic evolution of SARS-CoV-2 and the emergence of different variants, leading to therapeutic and immune evasion and survival of this genetically highly labile RNA virus. The nasopharyngeal persistence of infectious virus beyond 17 days proves its constant interaction with the human immune system and increases the intra-individual mutational possibilities. We performed a prospective high-throughput sequencing study (ARTIC Nanopore) of SARS-CoV-2 from so-called "persistent" patients, comparing them with a non-persistent population, and analyzing the quasi-species present in a single sample at time t. Global intra-individual variability in persistent patients was found to be higher than in controls (mean 5.3%, Standard deviation 0.9 versus 4.6% SD 0.3, respectively, p < 0.001). In the detailed analysis, we found a greater difference between persistent and non-persistent patie...
Chronic SARS-CoV-2 infection and viral evolution in a hypogammaglobulinaemic individual
2021
There is widespread interest in the capacity for SARS-CoV-2 evolution in the face of selective pressures from host immunity, either naturally acquired post-exposure or from vaccine acquired immunity. Allied to this is the potential for long perm persistent infections within immune compromised individuals to allow a broader range of viral evolution in the face of sub-optimal immune driven selective pressure. Here we report on an immunocompromised individual who is hypogammaglobulinaemic and was persistently infected with SARS-CoV-2 for over 290 days, the longest persistent infection recorded in the literature to date. During this time, nine samples of viral nucleic acid were obtained and analysed by next-generation sequencing. Initially only a single mutation (L179I) was detected in the spike protein relative to the prototypic SARS-CoV-2 Wuhan-Hu-1 isolate, with no further changes identified at day 58. However, by day 155 the spike protein had acquired a further four amino acid chang...
Despite seminal advances towards understanding its infection mechanism, SARS-CoV-2 continues to cause significant morbidity and mortality worldwide. Though mass immunization programs have been implemented in several countries, the viral transmission cycle has shown a continuous progression in the form of multiple waves. A constant change in the frequencies of dominant viral lineages, arising from the accumulation of nucleotide variations (NVs) through favourable selection, is understandably expected to be a major determinant of disease severity and possible vaccine escape. Indeed, worldwide efforts have been initiated to identify specific virus lineage(s) and/or NVs that may cause a severe clinical presentation or facilitate vaccination breakthrough. Since host genetics is expected to play a major role in shaping virus evolution, it is imperative to study role of genome-wide SARS-CoV-2 NVs across various populations. In the current study, we analysed the whole genome sequence of 354...
Genomic Evolution of SARS-CoV-2 Virus in Immunocompromised Patient, Ireland
Emerging Infectious Diseases, 2021
We examined virus genomic evolution in an immunocompromised patient with prolonged severe acute respiratory syndrome coronavirus 2 infection. Genomic sequencing revealed genetic variation during infection: 3 intrahost mutations and possible superinfection with a second strain of the virus. Prolonged infection in immunocompromised patients may lead to emergence of new virus variants.
EBioMedicine, 2021
Background: There is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses. Methods: We describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape. Findings: We found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape. Interpretation: Our results highlight the potential need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered.
Molnupiravir and Paxlovid are the only antivirals approved for COVID-19 treatment. Previous studies have evaluated their efficacy, tolerability, and viral clearance, but little is known about SARS-CoV-2 evolution under their pressure. Here the dynamics of genomic evolution of SARS-CoV-2 in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naïve individuals at 4 time-points (Day 0, Day 2, Day 5 of treatment and Day 7) were in-depth investigated. SARS-CoV-2 strains under Molnupiravir pressure were characterized by a higher genetic diversity compared to Paxlovid and no-drug pressure (mean ± SE: 18.66x10− 4±2.06x10− 4 vs. 3.34x10− 4±0.84x10− 4 vs. 3.10x10− 4±0.84x10− 4, P = 0.0003), with a peak between Day 2 and Day 5. Molnupiravir drove the emergence of more G-A and C-T transitions than other mutations (P = 0.031), regardless of SARS-CoV-2 genes. SARS-CoV-2 under Molnupiravir pressure did not show selective evolution different than that under Paxlovid or no-drug pressure, with the ...
SARS-CoV-2 presented moderately during two episodes of the infection with lack of antibody responses
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The world has gone through the critical phase of SARS-CoV-2 crisis caused by the new variants of the virus. The globally concerted effort to characterize viral genomic mutations across different clades has revealed several changes in the coding and also non-coding regions which might lead to a violent presentation or re-infection occurrence. Here, we studied a COVID-19 subject who represented the symptoms following the full recovery of the first infection. COVID-19 specific IgM and IgG were evaluated in both steps. The viral samples from oropharyngeal/ nasopharyngeal were subjected to RT-PCR and full sequencing was done in both incidences. The sequencing data was fully investigated with the reference sequence of SARS-CoV-2 and the changes were detected. The obtained data is in favor of re-infection with 128 days of interval. SARS-CoV-2 presented more severely in the second episode of the disease and the specific antibodies against COVID-19 were not detectable. Both infections were caused by the same clade 20G, however, the mutation rates were higher in the second incidence including 10 nucleotide substitutions which had rarely been reported before. In the present study, the nucleotide mutations in various regions of the viral genome have been presented. The re-infection could have significant effect on clinical implications as well as vaccination.
Communications Biology
Little is known about SARS-CoV-2 evolution under Molnupiravir and Paxlovid, the only antivirals approved for COVID-19 treatment. By investigating SARS-CoV-2 variability in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naïve individuals at 4 time-points (Days 0-2-5-7), a higher genetic distance is found under Molnupiravir pressure compared to Paxlovid and no-drug pressure (nucleotide-substitutions/site mean±Standard error: 18.7 × 10−4 ± 2.1 × 10−4 vs. 3.3 × 10−4 ± 0.8 × 10−4 vs. 3.1 × 10−4 ± 0.8 × 10−4, P = 0.0003), peaking between Day 2 and 5. Molnupiravir drives the emergence of more G-A and C-T transitions than other mutations (P = 0.031). SARS-CoV-2 selective evolution under Molnupiravir pressure does not differ from that under Paxlovid or no-drug pressure, except for orf8 (dN > dS, P = 0.001); few amino acid mutations are enriched at specific sites. No RNA-dependent RNA polymerase (RdRp) or main proteases (Mpro) mutations conferring resistance to Molnupiravir or Paxlo...