Extensive Intra-host evolution and T cell escape by SARS-CoV-2 in a 2.5-year persistent infection of an immunocompromised host

Read the full article See related articles

Listed in

This article is not in any list yet, why not save it to one of your lists.
Log in to save this article

Abstract

Persistent SARS-CoV-2 infection in immunocompromised patients creates a unique environment for the accumulation of mutations linked to immune evasion. This is due to prolonged virus-host interaction, coupled with the effects of diminished selective pressures resulting from suboptimal adaptive immunity. In this study, we investigated viral evolution and immune escape during a 2.5-year persistent SARS-CoV-2 infection in a patient with a history of multiple myeloma and rheumatoid arthritis on B cell depleting therapy. Sequencing of a SARS-CoV-2 virus isolate 899 days post-infection revealed a phylogenetic background compatible with the ancestral B.31 lineage. Nonetheless, the isolate displayed extensive intra-host evolution, evidenced by the accumulation of 56 non-synonymous mutations and one insertion across 20 viral proteins, as compared to the parental sequence. Apart from extensive private (infection-specific) mutations, the emergence of convergent mutations previously noted during other chronic infections and also in the later emerging variants of concern was observed. SARS-CoV-2-specific humoral immunity was undetectable in the patient; however, despite long-term antigen exposure, cellular immunity remained high in magnitude, functional, and responsive to peptide recall, without driving T cell dysfunction/exhaustion. T cell memory was broadly targeting but dominated by CD8+ T cells recognising the spike protein. No non-synonymous mutations accumulated in B cell epitopes, as expected. However, 38/56 were present in 93 CD4 and CD8 T cell epitopes. Computational models predicted reduced MHC binding or immunogenicity for 72% (40/55) of the CD8 epitopes affected. Importantly, functional assays confirmed T cell escape at 50% (1/2) and 86% (6/7) of the CD8 and CD4 epitopes tested in vitro. This study provides critical insights into viral adaptation and immune escape, demonstrating the ability of SARS-CoV-2 to explore a broad mutational landscape during long-term persistent infection, adapting to persistence and evolving within host to evade T cell recognition.

Article activity feed