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Circulating HERV type-W envelope proteins in post-COVID patients

The infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) can lead to a new disease called long-COVID-19 or post-acute COVID-19 syndrome (PACS). This syndrome can occur in various populations, including children, young adults, and those who had only mild COVID-19. Long/post-COVID, evidently represents a heterogeneous nosological entity, despite similar or overlapping symptoms between patients, and clear diagnostic criteria are yet to be established. In this pilot study, the authors from France and Spain investigated the presence of circulating human endogenous retrovirus type-W (HERV-W) envelope (ENV) proteins in patients with post-COVID syndrome, as well as the relationship between the expression of HERV-W ENV proteins and levels of anti-SARS-CoV-2 immunoglobulins. 

HERVs are relics derived from retroviruses that infected the human ancestral genome millions of years ago and were incorporated into the chromosomal DNA. HERVs have been vertically transmitted to offspring in a Mendelian fashion, constituting up to ~8% of the human genome. Usually, most HERVs are epigenetically silenced or silenced by a mutation.

However, they may be activated under certain conditions, including irradiation, chemical exposures, or exogenous viral factors. The aberrant expression of HERVs has been associated with conditions such as infectious, autoimmune, malignant, and neurological diseases. 

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, the spike (S), envelope (E), nucleocapsid (N), and membrane (M) protein. Like other infectious agents, SARS-CoV-2 can activate dormant HERV sequences ancestrally integrated in human genomes. A recent study has shown that SARS-CoV-2 can activate HERV type-W ENV proteins in a manner independent of the ACE2 receptor in cultured peripheral blood mononuclear cells of healthy blood donors. Furthermore, circulating HERV-W ENV proteins were identified in plasma or serum samples of all severe COVID-19 patients admitted to the ICU, and also in various postmortem tissues obtained from severe COVID-19 patients, including the lungs, heart, brain, nasal mucosa, and gastrointestinal tract.



About the study

The study included a total of 66 patients, 22 diagnosed with acute COVID-19, 12 diagnosed with post-COVID syndrome, 17 pre-pandemic cases of chronic fatigue syndrome, a disease with overlapping symptoms with post-COVID, 4 pre-pandemic healthy blood donors, and 11 healthy donors whose samples were taken during the pandemic. The acute COVID-19 patients were admitted to the hospital with a clinical disease ranging from moderate to severe. The symptoms registered in cases diagnosed with post-COVID syndrome lasted for a minimum of six months. 


Circulating detectable levels of HERV-W ENV proteins were found in 58% (7/12) of patients diagnosed with post-COVID syndrome, compared to 41% (9/22) of the acute COVID-19 group. According to the authors, higher proportions and values of HERV-W ENV expression in post-COVID cases than in acute COVID-19 cases might suggest a link between HERV-encoded proteins and post-COVID syndrome, or, more likely, with a subgroup of patients with related pathological consequences.

In post-COVID patients, the expression of HERV-W ENV proteins was detected 6 to 19 months after the acute infection, confirming that chronic expression of HERV-W ENV proteins is possible over one year after the acute infection. 

2/17 pre-pandemic participants with chronic fatigue syndrome were strongly positive for HERV-W ENV expression.

Patients with acute COVID-19 had increased anti-SARS-CoV-2 antibody response for all isotypes (IgG, IgM, IgA, and IgE). Total IgM level was elevated in 72% of patients, whereas 59% had elevated levels of total IgG, IgA, and IgE. Interestingly, in the acute COVID-19 group, increased IgG, IgM, and IgE levels were found in samples positive for HERV-W ENVs. As expected, pre-pandemic controls were negative for any of the anti-SARS-CoV-2 immunoglobulins. 

Post-COVID-19 cases still had significant levels of anti-SARS-CoV-2 S IgG, IgA, and remarkably above acute cases, IgE isotype, but not of the IgM isotype. Increased levels of anti-S IgG were detected in 58% of post-COVID cases, increased levels of anti-S Ig in 42% of cases, and increased levels of anti-N IgM in only 3 cases.

Interestingly, 75% of cases diagnosed with post-COVID had elevated levels of anti-S, and anti-N IgE antibodies compared to pre-pandemic controls. According to the authors, a sustained immune response against SARS-CoV-2 antigens was unexpectedly biased towards IgE reactivity in the post-COVID group.


The authors stated that two parameters are important in this pilot study. The first is HERV-W ENV antigenemia in 58% of post-COVID patients long after the acute SARS-CoV-2 infection. The second is a positive anti-SARS-CoV-2 IgE serology in 75% of cases diagnosed with post-COVID. 

This article was published in Frontiers in Immunology.

Journal Reference

Gimenez-Orenga K, et al. HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms. Front. Immunol. 2022; 13:1020064. (Open Access)

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