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A remarkable genetic diversity and intra-host evolution of the SARS-CoV-2 in individuals with advanced HIV infection

Previous studies have suggested that genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerge preferentially in immunocompromised individuals. However, the processes of intra-host evolution that produce them are not fully understood. A group of scientists from the United States, South Africa, and Canada developed a high-throughput, single-genome amplification and sequencing (HT-SGS) methodology to investigate the genetic diversity of the SARS-CoV-2 spike (S) protein in individuals infected with human immunodeficiency virus (HIV). The results showed that intra-host genetic diversity and evolution of the SARS-CoV-2 strikingly differed between individuals with advanced, poorly controlled HIV infection and those with controlled infection or uninfected, within days of the onset of COVID-19 symptoms.

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, namely the spike (S), envelope (E), nucleocapsid (N), and membrane (M) protein. Because of its key role in viral host recognition and entry, the S protein is a hot spot for mutations in emerging variants, characterized by increased viral fitness. 

The SARS-CoV-2 mutations were identified in individuals infected with HIV, weeks or months after the COVID-19 symptom onset, suggesting a temporal threshold after which SARS-CoV-2 has accumulated sufficient mutations to evolve within an individual. The authors emphasized a need to define the extent, kinetics, and evolutionary patterns of SARS-CoV-2 diversification in immunocompromised individuals to understand the emergence of new SARS-CoV-2 variants of concern (VOCs).

About the study

This study included 47 participants, 22 infected with HIV (18 hospitalized and 4 outpatients) and 25 uninfected (7 hospitalized for other reasons and 18 outpatients).

In the group of hospitalized HIV patients, ten had advanced HIV infection defined by peripheral blood CD4 T cell counts below 200 cells/μL. Among them, six patients had plasma HIV RNA of more than 105 copies/mL.

Of the remaining hospitalized HIV patients, five did not have available CD4 counts, and three had CD4 counts ≥200 cells/μL. In the outpatient cohort, two individuals infected with HIV had CD4 counts below 200 cells/μL and two had CD4 counts ≥200 cells/μL. 

To investigate the intra-host evolution of the SARS-CoV-2 during persistent HIV infection, the authors used a high-throughput, single-genome amplification and sequencing (HT-SGS) methodology to obtain up to ~103 gene sequences of the SARS-CoV-2 S protein from each of 184 respiratory samples from both cohorts.

Upper respiratory tract samples were taken from participants at the time of study enrollment, at a median of four days after the onset of COVID-19 symptoms, and every second day (hospitalized cohort) or three times weekly (outpatient cohort), until the cessation of SARS-CoV-2 RNA shedding.

Results

The HT-SGS methodology performed on 184 respiratory samples from 47 participants resulted in 70,968 single-genome sequences from individuals infected with HIV and 29,824 single-genome sequences from individuals without HIV. These single-genome sequences included 431 different single-nucleotide variations or deletions that defined 831 spike gene haplotypes.

In individuals with HIV and CD4 counts ≥200 cells/μL and uninfected individuals, the majority of single-genome S sequences in each individual matched one haplotype that predominated throughout the infection.

Individuals with advanced HIV infection exhibited intra-host SARS-CoV-2 S protein diversity with a median of 46 haplotypes per person, and rapid fluctuation of the composition of S sequences over time. Intra-host S protein diversity was significantly higher among individuals with advanced HIV than in uninfected individuals. In addition, higher intra-host S protein diversity immediately after the onset of COVID-19 symptoms in individuals infected with HIV predicted longer SARS-CoV-2 RNA shedding.

According to these findings, the permissiveness for SARS-CoV-2 replication in individuals with HIV and low CD4 counts, often accompanied by uncontrolled HIV viremia, was associated with high levels of the S protein genetic diversity within days of the onset of COVID-19 symptoms. The authors stated that the evolution of SARS-CoV-2 in individuals with advanced HIV infection is not only a product of random diversification through unchecked replication but also of intra-host adaptation that may significantly increase the risk of new VOCs.

Conclusion

This study has found that intra-host genetic diversity and evolution of the SARS-CoV-2 strikingly differed between individuals with advanced, poorly controlled HIV infection and those with controlled infection or uninfected. The authors concluded that a remarkable genetic diversity of the SARS-CoV-2 in individuals with advanced HIV infection suggests that adaptive intra-host SARS-CoV-2 evolution may markedly increase the risk for the emergence of new VOCs in these individuals.

They stated that further research is needed to comprehend whether intra-host SARS-CoV-2 variants that arise in individuals with HIV or other immunocompromising conditions differ in their potential to evade pre-existing immunity in immunocompetent individuals.

This study has been published on a preprint server and is currently being peer-reviewed.

 

Journal Reference

Hee Ko S, Radecki P, Belinky F et al. Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection. bioRxiv preprint.  https://doi.org/10.1101/2024.01.05.574420

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