Recombinant SARS-CoV-2 isolated from chronic COVID-19 patient

By on June 14, 2022 0

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has increased and decreased, depending on the level of immunity in the population and the biological characteristics of the virus. The emergence of new variants of the virus, with higher transmissibility or immune evasion characteristics, for example, has changed the course of the pandemic. A new research article in the journal Virus reports the isolation of a recombinant strain in a patient infected with the virus for more than a year.

Study: Sequential appearance and isolation of a SARS-CoV-2 recombinant between two major SARS-CoV-2 variants in a chronically infected immunocompromised patient. ​​​​​​Image credit: NIAID

Introduction

Genetic recombination refers to the combining of corresponding parts of a genomic molecule to form a new sequence. It commonly occurs in ribonucleic acid (RNA) viruses, including the currently circulating SARS-CoV-2, a member of the coronavirus family. In fact, it is suspected of having given rise to the pandemic virus.

This phenomenon has also been inferred to occur in human patients with this infection, as shown by the presence of distinctive mutations from different strains of the virus in the same patient. However, none of these have been isolated so far.

In the current article, published in the journal Virus, scientists found evidence of slow emergence of a recombinant strain of SARS-CoV-2 in a chronically immunocompromised patient. The patient was a 56-year-old man with lymphoma.

The first positive test came in August 2020, when he developed pneumonia, requiring admission to an intensive care unit (ICU). This was successfully treated, but the virus was not eliminated. In the last 14 months of his life, he repeatedly tested positive for the virus before dying of complications from lymphoma and progressive multifocal leukoencephalitis first diagnosed in May 2021.

The first detection of a hybrid-genome SARS-CoV-2 variant occurred after 14 months of infection. The two strains that had undergone recombination were identified as B.1.160 and the Alpha variant. Two regions of the first had been replaced by the second, and the spike gene showed the eight mutations characteristic of the Alpha variant, while the S477N mutation which is a characteristic of B.1.160 was absent.

There was little evidence to suggest that the presence of these Alpha mutations was due to co-infection or contamination with both variants. In place, “These results indicated that this mosaic genome was the result of recombinations between the parental genomes of variants B.1.160 and Alpha.”

The timeline of positive viral RNA tests suggested that the initial infection occurred with B.1.160, circulating widely from August 2020 to January 2021, when the Alpha variant replaced it. The next sequence was obtained only 8 months later, which showed that a mosaic genome had already formed between the two strains.

This recombinant formed in several steps, with recombination occurring at three sites on both parental genomes. The detection of multiple chimeric copies indicated the presence of several breakpoints between the ancestral strains.

Schematic representation of the structure of SARS-CoV-2 genomes obtained from nasopharyngeal swabs and culture supernatants, as well as recombination events over time, with reference to the parental genomes of B.1.160 and Alpha variants.  (a) Genome map and annotation;  (b) Genome structure and mutations.  The blue color of the rectangles indicates the sequences of a B.1.160 variant;  the yellow color indicates sequences of an Alpha variant;  the green color indicates codetection of sequences of a B.1.160 variant and an Alpha variant;  the gray color indicates sequences of undetermined origin.  The signature mutations of the B.1.160 and Alpha variants are indicated by a blue background and a yellow background, respectively.  Absent signature mutations are indicated by red font.  Δ21,765: -6 nucleotides;  Δ21,991: -3 nucleotides.  Nsp, non-structural protein;  ORF, open reading frame.

Schematic representation of the structure of SARS-CoV-2 genomes obtained from nasopharyngeal swabs and culture supernatants, as well as recombination events over time, with reference to the parental genomes of B.1.160 and Alpha variants. (a) Genome map and annotation; (b) Genome structure and mutations. The blue color of the rectangles indicates the sequences of a B.1.160 variant; the yellow color indicates sequences of an Alpha variant; the green color indicates codetection of sequences of a B.1.160 variant and an Alpha variant; the gray color indicates sequences of undetermined origin. The signature mutations of the B.1.160 and Alpha variants are indicated by a blue background and a yellow background, respectively. Absent signature mutations are indicated by red font. Δ21,765: -6 nucleotides; Δ21,991: -3 nucleotides. Nsp, non-structural protein; ORF, open reading frame.

What are the implications?

The results of this study highlighted the presence of recombination in an immunocompromised lymphoma patient who developed a prolonged course of SARS-CoV-2 infection despite multiple treatments. The result was the development of a hybrid viral strain formed by B.1.160 and the Alpha variant. Replacement of a distinctive B.1.160 mutation with multiple characteristic Alpha mutations between 8 and 14 months was considered non-accidental and the result of recombination at three sites.

Further analysis of genomic samples from successive respiratory swabs and cultures of the virus showed a stepwise development of several hybrid viruses in this patient, one of which established and continued to replicate in the host until the very end.

This first sampling study, which lasted more than a year, gives a lot of information on how RNA viruses recombine to form new strains, and in particular, reveals the generation of a SARS- Recombinant CoV-2 that has been isolated in culture. Previous research showed the presence of 16 Alpha-non-Alpha recombinants in 2021 in the UK. Others have suggested that recombinants account for 5% of circulating viruses in the UK and US.

Even as more and more recombinants are detected each month, researchers are exploring different pathways in various cell types or between different types of RNA viruses. This could help to understand how human pathogenic RNA viruses emerge.

The significance of such findings should “lead to a strengthening of genomic surveillance in patients, in particular in immunocompromised long-term carriers of the virus. Such infectious episodes could possibly lead to the emergence of new emerging viruses.”