Insights into Persistent SARS-CoV-2 Reservoirs in Chronic Long COVID

Long COVID (LC), also known as post-acute sequelae of COVID-19 infection (PASC), is a heterogeneous and debilitating chronic disease that currently affects 10 to 20 million people in the U.S. and over 420 million people globally. With no approved treatments, the long-term global health and economic impact of chronic LC remains high and growing. LC affects children, adolescents, and healthy adults and is characterized by over 200 diverse symptoms that persist for months to years after the acute COVID-19 infection is resolved. These symptoms target twelve major organ systems, causing dyspnea, vascular damage, cognitive impairments ("brain fog"), physical and mental fatigue, anxiety, and depression. This heterogeneity of LC symptoms, along with the lack of specific biomarkers and diagnostic tests, presents a significant challenge to the development of LC treatments. While several biological abnormalities have emerged as potential drivers of LC, a causative factor in a large subset of patients with LC, involves reservoirs of virus and/or viral RNA (vRNA) that persist months to years in multiple organs driving chronic inflammation, respiratory, muscular, cognitive, and cardiovascular damages, and provide continuous viral antigenic stimuli that overstimulate and exhaust CD4⁺ and CD8⁺ T cells. In this review, we (i) shed light on persisting virus and vRNA reservoirs detected, either directly (from biopsy, blood, stool, and autopsy samples) or indirectly through virus-specific B and T cell responses, in patients with LC and their association with the chronic symptomatology of LC; (ii) explore potential mechanisms of inflammation, immune evasion, and immune overstimulation in LC; (iii) review animal models of virus reservoirs in LC; (iv) discuss potential T cell immunotherapeutic strategies to reduce or eliminate persistent virus reservoirs, which would mitigate chronic inflammation and alleviate symptom severity in patients with LC.