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

## TL;DR

A study shows how SARS-CoV-2 evolved for 2.5 years in an immunocompromised person, leading to immune escape.

## Contribution

The paper reveals extensive viral evolution and T cell immune evasion in a long-term SARS-CoV-2 infection.

## Key findings

- SARS-CoV-2 evolved with 56 non-synonymous mutations across 20 proteins during 2.5 years of infection.
- T cell epitopes were affected by mutations, leading to immune escape in 50-86% of tested epitopes.
- High T cell memory was observed despite undetectable antibodies and inhibitory receptor expression.

## Abstract

Prolonged virus-host interaction and suboptimal immunity during persistent SARS-CoV-2 infection of immunocompromised patients enables viral adaptation. We investigated viral evolution and immune escape during a 2.5-year persistent infection in a patient with multiple myeloma and rheumatoid arthritis receiving anti-CD20 therapy. Virus isolated 899-days post-infection revealed an ancestral B.31 lineage with extensive evolution (56 non-synonymous mutations across 20 viral proteins). Many mutations were private or convergent with those seen in other persistent infections and later variants. SARS-CoV-2-specific antibodies were undetectable. Despite prolonged antigen exposure, T cell memory was functional high-in-magnitude and breadth, but with inhibitory receptor expression and dominant spike-specific CD8 response. 38/56 mutations occurred in T cell epitopes, reducing MHC binding or immunogenicity for 69% of CD8 epitopes affected. Importantly, functional assays confirmed T cell escape at 50% (1/2) and 86% (6/7) of CD8 and CD4 epitopes tested in vitro. These findings reveal extensive viral adaptation and T cell immune evasion during persistent infection.

•SARS-CoV-2 persisted for 2.5 years in an immunocompromised host, evolving extensively•Sequencing revealed ancestral B.31 lineage with 56 NS convergent and unique changes•High magnitude functional T cell memory induced, with high inhibitory R expression•Mutations negatively impacted CD4 and CD8 epitopes, leading to immune escape

SARS-CoV-2 persisted for 2.5 years in an immunocompromised host, evolving extensively

Sequencing revealed ancestral B.31 lineage with 56 NS convergent and unique changes

High magnitude functional T cell memory induced, with high inhibitory R expression

Mutations negatively impacted CD4 and CD8 epitopes, leading to immune escape

Immunology; Immunity; Virology; Sequence analysis