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

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 <i>in vitro</i>. These findings reveal extensive viral adaptation and T cell immune evasion during persistent infection.