Regulation of HERVs by Sars-Cov-2 and the potential association with the persistence of coagulopathy and thromboinflammation in Long-COVID.

Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome and can become transcriptionally derepressed under pathological conditions. HERV-K derepression has been reported in severe COVID-19 and associated with thromboinflammation, while HERV-W proteins and inflammatory markers have been detected in patients with Long COVID. Here, we investigated HERV regulation following SARS-CoV-2 infection and its potential association with persistent thromboinflammation in Long COVID. Survivors of moderate or severe COVID-19 were evaluated 30 days to 36 months after hospital discharge (CAAE 5523520.3.0000.5249). Plasma from 62 Long COVID patients evaluated 31–194 days after discharge (PCO1) and from a subgroup of 23 patients re-evaluated 2–3 years after infection (PCO2) were analyzed by RNA-seq and ELISA. Both PCO groups showed increased plasma levels of Tissue Factor, soluble P-selectin (sCD62p), ANG1, and PDGF compared with healthy controls, although sCD62p and ANG1 were lower in PCO2 than in PCO1. RNA-seq identified six HERV-related elements consistently upregulated in both PCO groups, with expression positively correlating with sCD62p and ANG1, suggesting persistent HERV upregulation associated with thromboinflammation. Because platelets are anucleate, we hypothesized that HERV expression detected following SARS-CoV-2 infection may originate in megakaryocytes (MKs), the precursor cells of platelets. We therefore investigated whether SARS-CoV-2-associated stimuli induce HERV upregulation in MKs. In vitro, mature human CD34⁺-derived MKs showed increased HERV expression following stimulation with IL-6 or SARS-CoV-2 Spike protein, accompanied by increased PF4 and TNF-α production. Together, our findings identify persistent HERV derepression following SARS-CoV-2 infection and support an association between HERV expression, megakaryocyte/platelet activation, and chronic thromboinflammation in Long COVID.