SARS-CoV-2 Mutant Proteins Inhibit T Cells’ Ability to Identify and Destroy Infected Cells

A deep sequencing study of SARS-CoV-2 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. The team from the Research Center for Molecular Medicine in Austria, published their findings in Science Immunology. 

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. These 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. Benedikt Agerer and colleagues 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.