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Increased circulating levels of HERV-W ENV proteins and proinflammatory cytokines in hospitalized patients with psychosis spectrum disorder positive for SARS-CoV-2

HERVs are retroviral elements acquired through the multiple integrations of exogenous retroviruses that infected the human ancestral genome millions of years ago. Usually, most HERVs have become silenced because of mutations such as substitutions, insertions, deletions, and epigenetic modifications. For a long time, HERVs were considered part of the “junk DNA. However, they may be activated under certain conditions, including irradiation, chemical exposures, or exogenous viral factors. In this study, the consortium of authors investigated a possible association between infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the expression of an envelope (ENV) proteins encoded by human endogenous retrovirus type W (HERV-W) in a group of hospitalized patients diagnosed with psychosis spectrum disorders who had no history of acute COVID-19 infection and had not been vaccinated against SARS-CoV-2. 

HERVs are roughly divided into three classes: Class I comprises gamma-retroviruses, including HERV-H, and HERV-W; Class II comprises beta-retroviruses, including HERV-K; Class III comprises foamy viruses, such as HERV-L and HERV-S. HERV-K is the most active and intact group of endogenous retroviruses within the genome of primates.

HERV genome consists of four essential genes (gag, pro, pol, and env). The env gene encodes ENV protein, which was shown to be neurotoxic. The same research team that conducted the present study demonstrated before that the HERV-W ENV proteins are capable of inducing glia- and cytokine-dependent changes in synaptic organization and plasticity of glutamate N-methyl-d-aspartate (NMDA) receptor. The expression of the HERV-W ENV protein in rat brains resulted in abnormal behavior, that was reversed and prevented by a specific anti-HERV-W ENV antibody. 

The HERV ENV proteins were detected in the blood of approximately one-half of patients diagnosed with schizophrenia and one-third of patients diagnosed with bipolar disorder. Schizophrenia and bipolar disorder share approximately 60% of genetic risk factors and exhibit similar brain structural abnormalities, such as reductions in total brain gray and white matter, and increased lateral ventricular volume. However, the molecular characteristics of HERV-W differ between schizophrenia, bipolar disorder, and multiple sclerosis, possibly reflecting different subsets of HERV-W elements being activated. Slokar G, Hasler G. Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia. Front Psychiatry. 2016 Jan 11;6:183.

Chronic viruses such as the Epstein–Barr virus induce the transcription of the env gene of HERV-K, suggesting that other viruses might also activate HERV transcription. HIV-1 and SARS-CoV-2 infection can lead to the up-regulation of HERV-K. In addition, SARS-CoV-2 induces the expression of the HERV-W ENV proteins, suggesting their involvement in the immunopathogenesis of certain COVID-19-associated syndromes.

About the study

The study included 48 hospitalized patients diagnosed with psychosis spectrum disorders (38 with schizophrenia, 10 with schizoaffective disorder) and a control group of 55 caregivers without COVID-19-related symptoms. The mean age of patients was 41.7 ± 12.7 years. 35% of the patients were women and 65% were men. The mean age of the control group was 42.9 ± 10.8 years, and 79 % were women.

The patients reported a negative history of COVID-19. The sera were collected during the first wave of COVID-19 in the spring of 2020 before the vaccines against COVID-19 were available.


Although patients and controls reported a negative history of COVID-19, a positive anti-SARS-CoV-2 serology has been detected in both groups, indicating either a prior infection or a significant response following the exposure to SARS-CoV-2. Compared to controls, hospitalized patients with psychosis spectrum disorders had a significantly higher number of positive sera and a higher titer of specific anti-SARS-CoV-2 antibodies.

Hospitalized patients diagnosed with psychosis spectrum disorders had higher levels of circulating HERV-W ENV proteins than the control group. Importantly, HERV-W ENVs were detected only in seropositive participants in both groups of participants.

In the group of hospitalized patients with psychosis spectrum disorders, a significantly higher proportion of SARS-CoV-2 seropositive participants was positive for HERV-W ENV (27%, 13 of 48 participants) compared to the control group (9%, 5 of 55 participants).

Further categorization of patients with psychosis spectrum disorders into three clusters based on the following variables: SARS-CoV-2 seropositivity, HERV-W ENV positivity, and the levels of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α revealed significant results. In cluster 1 (17%; 8 of 48 participants), all patients were negative for SARS-CoV-2 and HERV-W ENV and had low serum levels of proinflammatory cytokines. In cluster 2 (56%; 27 of 48 participants), all patients were positive for SARS-CoV-2 but negative for HERV-W ENV and had low/intermediate levels of proinflammatory cytokines. In cluster 3 (27%; 13 of 48 participants), all patients were positive for all clustering variables and had higher levels of proinflammatory cytokines TNF-α, IL-8, and IL-6  than the two other clusters. The level of IL-1β differed significantly between cluster 3 and 1, and it was negative in all control subjects. 

According to these findings, SARS-CoV-2 and HERV-W ENV positivity were associated with high serum levels of proinflammatory cytokines in hospitalized patients diagnosed with psychosis spectrum


This study demonstrated increased levels of HERV-W ENV proteins and pro-inflammatory cytokines in hospitalized SARS-CoV-2-positive patients with psychosis spectrum disorders. The finding of HERV-W ENVs only in seropositive patients suggests a strong link between HERV-W activation, cytokine expression, and SARS-CoV-2 infection. Since the underlying mechanism remains unclear, the observed connection between this viral infection and HERV-W ENV and cytokine expression in patients with psychosis spectrum disorder requires further investigation.

This article was published in Translational Medicine.

Journal Reference

Tamouza R et al. Patients with psychosis spectrum disorders hospitalized during the COVID-19 pandemic unravel overlooked SARS-CoV-2 past infection clustering with HERV-W ENV expression and chronic inflammation. Translational Psychiatry (2023) 13:272. (Open Access)

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