Chronic viral infections are ubiquitous in humans, with individuals carrying multiple viruses that can reactivate during physiological stress, including severe illness1. Notably, SARS-CoV-2 infection has been shown to reactivate chronic viruses such as Epstein–Barr virus and cytomegalovirus, yet the full extent, temporal dynamics and immunological impact of viral reactivation in COVID-19 remain incompletely understood2, 3, 4, 5, 6–7. Here, leveraging multi-omic longitudinal data from 1,154 hospitalized patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, we reveal significant reactivation of Herpesviridae and Anelloviridae during acute COVID-19, with distinct temporal dynamics for different viruses, and demonstrate that reactivation correlates with disease severity, host immune effects and clinical outcomes. Although our results do not establish causation between virus reactivation and clinical outcomes, we highlight the prevalence of chronic viral reactivation during acute COVID-19 and long COVID. Our findings challenge the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression, demonstrating that reactivations occur frequently in immunocompetent individuals during severe illness and in association with increased systemic inflammation. Additionally, we demonstrate persistence of viral reactivation in convalescence, and report an association of Anelloviridae with long COVID. This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID. Chronic reactivation of distinct herpesviruses and anelloviruses occur during acute and long COVID-19, and track with disease severity, inflammation and outcomes, revealing immune signatures with prognostic potential.
Cole P. Maguire, Jing Chen, Nadine Rouphael et al.· Nature· 3 citations
Despite suppressive antiretroviral therapy (ART), HIV reservoirs rapidly rebound upon treatment interruption, driven in part by progressive dysfunction of HIV-specific CD8+ T cells. Current strategies targting CD8+T cell dysfunction in cancer show limited benefit in people living with HIV (PLWH), underscoring the need for alternative approaches tailored to the unique immunological landscape of HIV infection. Adenosine (ADO) signaling is a potent immunoregulatory pathway regulated by adenosine deaminase-1 (ADA-1) that becomes dysregulated in PLWH and is associated with viral persistence. However, more work is needed to define its direct contribution to HIV-specific CD8+ T-cell dysfunction.
Using primary samples from PLWH, we applied three complementary approaches: (1) multi-omic and phenotypic profiling of tetramer-sorted HIV- and CMV-specific CD8+ T cells to assess regulation of ADA and ADO-signaling components; (2) ex vivo functional assays measuring cytokine production and degranulation following ADO or 2-chloroadenosine exposure with ADA-1 inhibition; and (3) CD8-targeted lipid nanoparticles (CD8-ADA-LNPs) to selectively deliver ADA-1 mRNA and assess functional improvement.
HIV-specific CD8+ T cells exhibited repression of the ADA locus, increased expression of CD39 and the A2a adenosine receptor, indicating potential heightened sensitivity to ADO-mediated suppression. Functionally, ADO-exposure impaired CD8+ T-cell function, dependent on ADA-1. Targeted ADA-1 mRNA delivery via CD8-ADA-LNPs restored ADA-1 expression and improved antigen-specific CD8+ T-cell function in PLWH ex vivo.
These findings identify dysregulated ADO signaling and ADA-1 deficiency as contributors to HIV-specific CD8+ T-cell dysfunction and establish targeted ADA-1 delivery as a novel strategy to enhance CD8+ T-cell function. This approach provides a framework for targeting ADO-mediated immune suppression of CD8+T cells in HIV and other disease landscapes, including cancer.
Part of this work was funded by NIH grant to Dr. Elias K Haddad (# U19AI128910-04S1)
Translational and Interventional Immunology (TI)
Arden O. Edgerton, Dillon O'Neill, David Joyner et al.· Journal of Immunology· 0 citations
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