Fournelle, D. | Search bioRxiv

bioRxiv2022

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

Throughout the SARS-CoV-2 pandemic, several variants of concern (VOC) have been identified, many of which share recurrent mutations in the spike proteins 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.

genomics↗

bioRxiv2021

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

The rapid, global dispersion of SARS-CoV-2 since its initial identification in December 2019 has led to the emergence of a diverse range of variants. The initial concerns regarding the virus were quickly compounded with concerns relating to the impact of its mutated forms on viral infectivity, pathogenicity and immunogenicity. To address the latter, we seek to understand how the mutational landscape of SARS-CoV-2 has shaped HLA-restricted T cell immunity at the population level during the first year of the pandemic, before mass vaccination. We analyzed a total of 330,246 high quality SARS-CoV-2 genome assemblies sampled across 143 countries and all major continents. Strikingly, we found that specific mutational patterns in SARS-CoV-2 diversify T cell epitopes in an HLA supertype-dependent manner. In fact, we observed that proline residues are preferentially removed from the proteome of prevalent mutants, leading to a predicted global loss of SARS-CoV-2 T cell epitopes in individuals expressing HLA-B alleles of the B7 supertype family. In addition, we show that this predicted global loss of epitopes is largely driven by a dominant C-to-U mutation type at the RNA level. These results indicate that B7 supertype-associated epitopes, including the most immunodominant ones, were more likely to escape CD8+ T cell immunosurveillance during the first year of the pandemic. Together, our study lays the foundation to help understand how SARS-CoV-2 mutants shape the repertoire of T cell targets and T cell immunity across human populations. The proposed theoretical framework has implications in viral evolution, disease severity, vaccine resistance and herd immunity.

immunology↗