Herpesvirus reactivation in COVID-19: clinical evidence, mechanistic insights, and research gaps

Abstract

Herpesviruses establish lifelong latency and can reactivate when antiviral immune surveillance is compromised. Since the onset of COVID-19 pandemic, reactivation of multiple human herpesviruses has increasingly been documented, particularly in patients with severe or critical illness. Herpesvirus reactivation has been associated with prolonged intensive care unit stays, secondary infections, greater ventilatory support requirements, and increased mortality. This review summarizes the latency and reactivation characteristics of the major human herpesviruses and evaluates the clinical evidence linking their reactivation to SARS-CoV-2 infection. We further propose a multifactorial mechanistic framework involving impaired T-cell and natural killer cell surveillance, defective interferon-mediated immunity, sustained inflammation and cytokine signaling, direct and indirect effects of SARS-CoV-2 proteins, and host transcriptional and epigenetic reprogramming. However, despite accumulating clinical and experimental evidence supporting a biologically plausible association between SARS-CoV-2 infection and herpesvirus reactivation, the precise mechanisms underlying this interplay remain incompletely understood. Longitudinal viral monitoring, physiologically relevant latency models, and mechanistic intervention studies are therefore needed to establish causality and identify patients who may benefit from targeted surveillance or antiviral treatment.