A deep sequencing study of 747 SARS-CoV-2 virus isolates has revealed mutant peptides derived from the virus that cannot effectively bind to critical proteins on the surface of infected cells and, in turn, hamper activation of CD8⁺ killer T cells that recognize and destroy these infected cells. These peptides, the authors say, represent one way the coronavirus subverts killer T cell responses and stymies immunity in the host.

Their results may be of particular importance for SARS-CoV-2 subunit vaccines, such as the RNA vaccines currently in use, which induce responses against a limited number of viral peptides presented on T cells; such vaccines may be at risk of stunted efficacy if any of these target peptides are mutated in emerging virus variants.

However, because T cells can broadly recognize an array of epitopes, it remains to be determined just how mutations in single epitopes truly affect viral control. Killer T cells kill infected cells upon recognition of viral epitopes, which are displayed on the surface of infected cells by class I major histocompatibility complex (MHC-I) proteins, or human leukocyte antigen (HLA) proteins as they’re called in humans. Certain positions in these epitopes are critical for HLA-I presentation, and mutations in these regions might interfere with the epitope binding to the HLA.

Benedikt Agerer and colleagues identified mutations in killer T cell epitopes from SARS-CoV-2 after deep sequencing 747 SARS-CoV-2 virus isolates. They confirmed that these mutant peptides could not effectively bind to HLA protein in a cell-free, in vitro assay. When exposed to killer T cells isolated from HLA-matched COVID-19 patients, reduced binding of mutant peptides to HLA-I decreased proliferation of T cells, stunted production of inflammatory factors such as IFN-γ, and interrupted the overall cell-killing activity of the killer T cells.

In future work, the authors aim to address how these “escape” mutations are maintained during transmission between individuals with differing HLA subtypes and how viruses carrying epitope mutations affect disease severity.

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