PolyBio-supported research provides new evidence that Long COVID is characterized by ongoing immune responses to persistent viral proteins, further supporting the role of viral persistence and herpesvirus reactivation in the disease process.
Project lead Dr. Nadia Roan
A new study supported by the PolyBio Research Foundation has found that people with Long COVID harbor persistent populations of highly cytolytic CD8+ T cells directed against SARS-CoV-2 but also the herpesviruses Epstein-Barr virus (EBV) and cytomegalovirus (CMV). The findings suggest that Long COVID is characterized by an ongoing immune response to persistent viral proteins, which are most likely produced during the continued persistence or reactivation of these viruses within the body. The study adds to a growing body of research indicating that SARS-CoV-2 persistence and herpesvirus reactivation contribute to Long COVID pathogenesis.
Published in Cell Reports Medicine, the study used an advanced combinatorial tetramer platform to profile virus-specific CD8+ T cells with unprecedented resolution. Unlike conventional approaches that stimulate immune cells before analysis, this technology enabled researchers to examine virus-specific T cells in their native state while simultaneously characterizing responses against dozens of viral targets.
Researchers at Gladstone Institutes and the University of California, San Francisco found that individuals who recovered from COVID-19 showed the expected decline in cytolytic T cell activity over time. In contrast, people with Long COVID retained elevated populations of virus-specific T cells expressing granzyme B and other markers of terminal differentiation and chronic stimulation months after infection. These abnormalities were observed in T cells recognizing SARS-CoV-2, EBV, and CMV, suggesting that persistent immune activation may involve multiple viruses rather than a single pathogen.
This study found several phenotypic differences in persistent-virus-specific CD8+ T cells in individuals with Long COVID compared to COVID-recovered controls. For example, those from Long COVID participants with were preferentially of the Tcm phenotype and dis-enriched for Temra cells, compared to COVID-recovered participants.
The authors propose that these persistent antiviral T cell responses reflect an inability to fully resolve the immune response following initial COVID-19 infection. Instead of transitioning into long-lived resting memory cells, virus-specific CD8+ T cells remain in a highly cytolytic state consistent with the immune response seen during an active viral infection. The study also identified a loss of stem-like memory CD8+ T cells in people with Long COVID, suggesting that ongoing viral protein production may reshape the immune system over time.
By applying next-generation technologies to study pathogen-specific immunity, this research provides important new insight into the biological mechanisms underlying Long COVID and demonstrates how advanced immune profiling can reveal disease processes that would otherwise remain hidden. In this case CD8+ T cells in Long COVID individuals that were specific to SARS-CoV-2, CMV, both SARS-CoV-2 and CMV, or EBV were terminally differentiated, cytolytic, and exhausted, and exhibited signs consistent with immunosenescence and/or aging.
PolyBio is proud to have supported this work as part of its mission to accelerate discoveries that advance the diagnosis and treatment of Long COVID and other infection-associated chronic diseases.
About PolyBio Research Foundation
PolyBio Research Foundation is a 501(c)(3) organization advancing research on how viral, bacterial, and parasitic infections drive chronic disease and aging. We build collaborative projects that identify, diagnose, and treat root causes of infection-associated chronic illness.